Glepaglutide Clears EMA Gate, But HTA Cost-Effectiveness Wall Looms Large

Zealand Pharma's Zeydovio Receives Positive CHMP Opinion for SBS

Zealand Pharma announced that the CHMP of the European Medicines Agency issued a positive opinion, recommending marketing authorization for Zeydovio™ (glepaglutide) for adults with short bowel syndrome (SBS). This marks the first major advancement in SBS treatment in Europe in over a decade. The recommendation is based on data from the pivotal Phase 3 EASE-1 trial, where twice-weekly glepaglutide significantly reduced parenteral support requirements. Two-thirds of patients achieved at least a 20% reduction in weekly parenteral support volume, and 14% achieved enteral autonomy after 24 weeks. The European Commission is expected to make a final decision within approximately 67 days.

• The positive CHMP opinion for Zeydovio™ (glepaglutide) signifies a crucial regulatory milestone, being the first major advancement in European short bowel syndrome (SBS) treatment in over ten years. This recommendation for marketing authorization by the European Medicines Agency paves the way for potential approval across the EU, Iceland, Liechtenstein, and Norway, with a final decision from the European Commission anticipated within approximately 67 days. This development offers new hope for thousands of patients burdened by chronic parenteral support dependence.
• The CHMP's recommendation is underpinned by robust data from the pivotal Phase 3 EASE-1 trial. In this study, twice-weekly glepaglutide demonstrated statistically significant and superior reductions in parenteral support (PS) requirements compared to placebo. A notable 65.7% of patients achieved a clinical response, defined as at least a 20% reduction in weekly PS volume at 24 weeks. Furthermore, 14% of patients treated with glepaglutide twice weekly achieved complete enteral autonomy, eliminating their need for PS entirely.
• Zeydovio™ (glepaglutide) is a long-acting GLP-2 analog designed to improve intestinal function and reduce parenteral support dependence. Its convenient twice-weekly subcutaneous administration via a ready-to-use autoinjector aims to ease disease management. Beyond the EASE-1 trial, the positive opinion is supported by long-term extension trials (EASE-2, EASE-3) and a mechanistic trial (EASE-4). Zealand Pharma is also actively enrolling patients in the Phase 3 EASE-5 trial to support a U.S. regulatory submission, indicating a comprehensive global development and commercialization strategy.

The Daily Burden of SBS and Limitations of Current Care

Current treatment approaches for short bowel syndrome (SBS) center on long-term parenteral nutrition (PN), which sustains patients but carries a substantial burden of complications and dependency. Emerging pharmacological options such as teduglutide offer meaningful reductions in PN requirements, yet introduce their own unresolved safety questions that complicate long-term use.

• PN-associated complications: Long-term PN is accompanied by severe complications including catheter-related bloodstream infection (CRBSI) and intestinal failure-associated liver disease (IFALD), and is associated with high healthcare costs. In pediatric cohorts on home parenteral nutrition, IFALD was recorded in 20% of patients and CRBSI at a rate of 4 per 1,000 PN days in earlier periods, though outcomes have improved over time.

• Central venous access risks: Delivery of PN requires long-term central venous access. Surgically placed central venous catheters carry complications that can lead to significant morbidity, including CRBSI and venous thrombosis, necessitating evaluation of alternative access strategies such as peripherally inserted central catheters (PICCs).

• Tolerability and safety concerns with teduglutide: Teduglutide, the GLP-2 analog approved for SBS, has been shown to be well tolerated for up to 30 months, but tolerability for even longer periods of treatment has not been examined. Safety concerns about possible carcinogenic properties during long-term use require ongoing evaluation, as studies in rodents have shown that exogenously administered GLP-2 increases the growth and incidence of adenomas in the colon, and the association between exogenous GLP-2 treatment and intestinal neoplasia in humans has not been fully identified.

• Metabolic complexity in pediatric SBS: Pediatric SBS patients on long-term PN exhibit distinct plasma metabolomic signatures, with significantly increased levels of glutamine compared to those in the short-term PN group, and alterations in amino acid metabolism and cell death pathways. These findings underscore the metabolic complexity of the condition and the challenge of identifying which patients will require prolonged PN support.

The EASE Program: Clinical Evidence Supporting Zeydovio's Efficacy

Several randomized, placebo-controlled and observational trials have evaluated teduglutide in adults with short bowel syndrome with intestinal failure (SBS-IF), establishing a consistent evidence base across dose regimens, geographies, and treatment durations. The primary efficacy endpoint across pivotal studies was the proportion of responders — defined as patients achieving ≥20% reduction in parenteral support (PS) volume from baseline at weeks 20 and 24 — with secondary endpoints capturing absolute PS volume reduction, days off PS per week, and biomarkers of intestinal adaptation.

Zeydovio's Impact on the Evolving SBS Treatment Landscape

Over the past five years, the short bowel syndrome (SBS) treatment landscape has been shaped substantially by accumulating evidence on glucagon-like peptide-2 (GLP-2) analogues — most notably teduglutide — across both adult and paediatric populations. A 2025 systematic review and meta-analysis of 4 randomised controlled trials enrolling 283 patients demonstrated that GLP-2 analogues produced a significantly greater reduction in weekly parenteral support (PS) volume compared with placebo (SMD -0.54; 95% CI -0.71 to -0.36; p=0.0022; I²=0%), and more frequently achieved reductions in PS of ≥1 day/week (RR 2.27; 95% CI 1.59 to 3.26; p=0.0219; I²=0%). No significant differences were observed in enteral autonomy (RR 4.21; 95% CI 0.00 to 280351.17; p=0.3479) or clinical response — defined as a ≥20% reduction in weekly PS volume sustained through weeks 20 and 24 — between GLP-2 analogue and placebo groups. Complementing this, phase III data from Japanese adult patients with SBS and intestinal failure (SBS-IF) showed mean PS volume reductions from baseline of -30.1 ± 25.9% at 24 weeks in TED-C14-004 and -25.6 ± 25.5% in SHP633-306, extending to -57.08 ± 28.49% at a 4.5-year interim data cut-off in the extension study SHP633-307 — findings consistent with prior international studies and without new population-specific safety signals.

The evidence base has also expanded meaningfully into paediatric SBS-IF, where long-term real-world data were previously scarce. A 2024 Spanish multicentre prospective study of 31 children (median age at treatment initiation 2.3 years; median treatment duration 19 months) reported that 80% achieved a >20% reduction in weekly parenteral nutrition (PN) energy and 77% achieved a >20% reduction in weekly PN volume. Among responders, 29% were fully weaned from PN, with a median treatment duration to weaning of 6 months. Critically, younger age at treatment initiation was the only statistically significant predictor of response (p=0.028), establishing an evidence-based rationale for earlier intervention. A 2025 case report further documented the first known instance of teduglutide use exceeding 6 years in a paediatric patient, resulting in complete PN independence despite a residual small bowel length of 9 cm — underscoring the potential for sustained intestinal adaptation with prolonged therapy.

Beyond efficacy endpoints, the field has increasingly recognised the importance of quality of life (QoL) and real-world treatment optimisation. A 2023 nested matched-pair real-world study demonstrated significant improvements in both SBS-QoL subscale and sum scores, as well as SF-36 physical and mental component summary scores (all p<0.02), over a median teduglutide treatment duration of 4.3 years — with no significant QoL changes observed in matched non-treated controls (SF-36 between-group differences: p=0.031 and p=0.012). Concurrently, a 2024 international survey of 19 expert intestinal failure centres revealed that only 10% of SBS-IF patients were receiving GLP-2 analogue therapy despite an estimated 30% eligibility rate, with most centres initiating treatment 6–12 months post-resection. Response assessment most commonly relied on a >20% PS decrease (95% of centres), ≥1-day/week PS reduction (84%), and increased urinary output (68%). Together, these data reflect a treatment landscape that has matured from proof-of-concept to real-world integration, while highlighting persistent gaps in access and standardisation of care.

Zeydovio's CHMP Nod: Reshaping Europe's SBS Treatment Landscape

The European Medicines Agency's CHMP positive opinion for Zeydovio™ (glepaglutide) marks a pivotal moment for adults living with short bowel syndrome (SBS) in Europe. For over a decade, significant advancements in this challenging condition have been scarce, leaving many patients reliant on burdensome parenteral support (PS). Glepaglutide, a long-acting glucagon-like peptide-2 (GLP-2) analog, is poised to change this landscape.

GLP-2 agonists work by enhancing intestinal adaptation and absorption, ultimately reducing the need for external nutritional support. The Phase 3 EASE-1 trial demonstrated that twice-weekly glepaglutide significantly reduced PS volumes, with a remarkable two-thirds of patients achieving at least a 20% reduction and 14% achieving complete enteral autonomy. This level of clinical benefit, coupled with a twice-weekly subcutaneous injection, offers a substantial convenience advantage over existing daily therapies, potentially improving patient quality of life and reducing the complications associated with long-term PS.

However, the evolving competitive landscape warrants consideration. While glepaglutide offers a less frequent dosing schedule than the established daily GLP-2 agonist, teduglutide, other novel GLP-2 analogs with even longer half-lives are in development, potentially offering even less frequent dosing in the future. Furthermore, it's important to note that while the twice-weekly regimen proved highly effective, the once-weekly glepaglutide regimen did not achieve statistical significance in the pivotal trial, suggesting that optimal dosing frequency is critical for maximizing patient outcomes. As glepaglutide moves towards final European Commission approval, the medical community will be keen to see how it integrates into clinical practice and how long-term real-world data further defines its role amidst a growing class of intestinotrophic therapies.