Glepaglutide Clears EMA Bar, But HTA Reimbursement Remains the Defining Test

CHMP Recommends Zeydovio for Short Bowel Syndrome

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has issued a positive opinion recommending marketing authorization for Zealand Pharma's 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, which showed statistically significant reductions in parenteral support requirements. In EASE-1, 65.7% of patients treated with twice-weekly glepaglutide achieved at least a 20% reduction in weekly parenteral support volume, and 14% achieved enteral autonomy after 24 weeks.

• The positive CHMP opinion for Zeydovio (glepaglutide) represents a significant regulatory advancement, being the first major development in short bowel syndrome treatment in Europe in over ten years. This recommendation paves the way for potential marketing authorization across the European Union, Iceland, Liechtenstein, and Norway, following review by the European Commission.
• Data from the pivotal Phase 3 EASE-1 trial demonstrated glepaglutide's superior efficacy. Patients receiving twice-weekly glepaglutide experienced a statistically significant reduction of 5.13 liters/week in parenteral support volume compared to placebo. Crucially, 65.7% achieved a clinical response (defined as at least a 20% reduction in weekly PS volume), and 14% of patients achieved complete enteral autonomy, eliminating the need for parenteral support entirely.
• Zeydovio offers a patient-friendly, twice-weekly subcutaneous administration via a ready-to-use autoinjector, potentially easing the burden of disease management for thousands of patients. Beyond Europe, Zealand Pharma is actively enrolling patients in the Phase 3 EASE-5 trial to gather further confirmatory evidence for a U.S. regulatory submission, indicating a global development strategy.

Addressing Key Challenges in Short Bowel Syndrome Treatment

Short bowel syndrome (SBS) presents a complex therapeutic landscape in which no single intervention reliably restores intestinal autonomy, and most patients require long-term, multimodal management. Dietary modifications and pharmacologic therapies are rarely sufficient on their own to eliminate dependence on parenteral nutrition (PN), while more advanced options carry substantial risks and limitations.

• Long-term PN dependence and associated complications: Home PN (HPN) remains the mainstay of treatment for severe SBS, yet it is associated with significant morbidity. Central venous access complications include catheter-related bloodstream infections, thrombosis, and progressive loss of venous access over time. PN itself can drive intestinal failure-associated liver disease (IFALD) and hyperglycemia, and HPN significantly impacts quality of life.

• Limitations of teduglutide, the primary pharmacologic advance: While the GLP-2 analogue teduglutide reduces PN volume requirements and can support weaning toward enteral autonomy, it is not universally effective and is contraindicated in patients with active gastrointestinal malignancies due to concern for malignancy development. Adverse effects reported in trials include abdominal pain or distention, injection site reactions, nausea, headaches, and fluid overload.

• Surgical options carry significant constraints: Autologous gastrointestinal reconstruction (AGIR) requires highly specialized multidisciplinary care in intestinal rehabilitation units, and re-anastomosis in the presence of abdominal contamination carries a high failure risk. Intestinal transplantation, while clinically accepted, is limited by high rates of graft loss, with 3-year actuarial patient survival remaining unchanged over two decades; outcomes for intestinal retransplantation are poor due to immunologic factors and patient debility.

• Pediatric-specific challenges: In infants and children, SBS with chronic intestinal failure is rare and complex, requiring long-term central venous access that carries risks of catheter infections, liver disease, and thrombosis. Peripherally inserted central catheters (PICCs) offer some advantage over surgically placed central venous catheters — including placement without general anesthesia — but catheter-related bloodstream infection rates of 5.3/1000 catheter days and venous thrombosis rates of 2.0/1000 catheter days remain clinically significant concerns.

Key Clinical Evidence Supporting Zeydovio™ in SBS

Several clinical trials and real-world studies have evaluated teduglutide in adults and pediatric patients with short bowel syndrome-associated intestinal failure (SBS-IF), examining parenteral support (PS) reduction, enteral autonomy, and safety across varied patient populations and treatment durations.

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Zeydovio™'s Place in the Evolving SBS Treatment Landscape

Over the past five years, the treatment landscape for short bowel syndrome (SBS) has been shaped substantially by accumulating evidence on glucagon-like peptide-2 (GLP-2) analogues, particularly teduglutide. A 2025 systematic review and meta-analysis of 4 randomized controlled trials encompassing 283 patients demonstrated that GLP-2 analogues produced a significantly greater weekly absolute parenteral support (PS) volume reduction compared with placebo (SMD -0.54; 95% CI -0.71 to -0.36; p=0.0022), and more frequently achieved reductions in PS of ≥1 day/week (RR 2.27; 95% CI 1.59 to 3.26; p=0.0219). No significant differences were observed in enteral autonomy or clinical response — defined as a ≥20% reduction in weekly PS volume from baseline sustained through weeks 20 and 24 — between GLP-2 analogue and placebo groups, underscoring that while PS reduction is robust, full enteral independence remains a more selective outcome. Complementing this, a 2024 international real-world survey of expert intestinal failure centers found that only 10% of SBS-IF patients were receiving GLP-2 analogues despite an estimated 30% being eligible, with most centers initiating therapy 6–12 months after the last intestinal resection and using >20% PS decrease, ≥1 day/week PS reduction, and increased urinary output as the primary response criteria.

Evidence has also expanded into previously underrepresented populations, most notably pediatric patients and non-Western cohorts. A 2024 Spanish multicenter prospective study of 31 pediatric patients reported that 80% achieved a >20% reduction in weekly PN energy and 77% achieved a >20% reduction in weekly PN volume, with 9 patients (29%) achieving full PN weaning at a median treatment duration of 6 months. Critically, younger age at treatment initiation was the only statistically significant predictor of response (p=0.028), establishing early intervention as a clinically meaningful strategic consideration. A 2025 pediatric case report further documented complete PN weaning following more than 6 years of teduglutide therapy in a child with a residual small bowel length of 9 cm — representing the longest reported duration of teduglutide use in a pediatric patient in clinical trials. In the Japanese adult population, phase III data from studies TED-C14-004 and SHP633-306, with extension SHP633-307, showed mean PS volume reductions of -30.1 ± 25.9% and -25.6 ± 25.5% at 24 weeks, respectively, deepening to -57.08 ± 28.49% at a 4.5-year interim data cut-off, with no new population-specific safety signals identified.

Beyond efficacy and safety endpoints, the evidence base has broadened to encompass patient-reported outcomes and quality of life (QoL). A 2023 nested matched-pair real-world study with a median teduglutide treatment duration of 4.3 years demonstrated significant improvements in both SBS-QoL subscales and sum score, as well as SF-36 physical and mental component summary scores (all p<0.02) in teduglutide-treated patients, while matched non-treated controls showed no significant changes in any of these measures. Significant between-group differences in QoL change were observed for both SF-36 summary scores (p=0.031 and p=0.012), providing the first real-world demonstration that teduglutide treatment translates into meaningful QoL gains relative to untreated SBS-IF patients. Collectively, this body of evidence reflects a treatment landscape increasingly defined by long-term, individualized GLP-2 analogue therapy, with growing recognition that response assessment, treatment timing, and patient selection are as consequential as the pharmacological mechanism itself.

Glepaglutide's European Approval: Redefining SBS Patient Care

The recent positive opinion from the European Medicines Agency's CHMP for Zealand Pharma's glepaglutide (Zeydovio) marks a significant moment for adults living with short bowel syndrome (SBS) in Europe. This recommendation, the first major advancement in SBS treatment in the region in over a decade, signals a new era for patients grappling with the severe burden of parenteral support (PS) dependency.

Glepaglutide, a novel long-acting glucagon-like peptide-2 (GLP-2) analogue, builds upon the established mechanism of intestinal adaptation but offers a crucial differentiator: a twice-weekly subcutaneous dosing schedule. This is a notable improvement over existing daily GLP-2 agonists, potentially enhancing patient adherence and overall quality of life by reducing the frequency of injections. The pivotal Phase 3 EASE-1 trial underscored its clinical value, demonstrating:

• Statistically significant reductions in weekly PS volume.

• 65.7% of patients achieving at least a 20% reduction in PS volume.

• A remarkable 14% of patients achieving complete enteral autonomy after 24 weeks.

While glepaglutide's twice-weekly regimen offers a clear advantage, the competitive landscape for GLP-2 agonists is evolving. Newer agents, such as apraglutide, are characterized by even longer half-lives, potentially enabling once-weekly or less frequent dosing, which could challenge glepaglutide's market position in the future. Furthermore, while the EASE-1 trial showed robust efficacy for twice-weekly dosing, the once-weekly regimen did not meet statistical significance for key endpoints, suggesting that the optimal balance between dosing frequency and clinical benefit is critical. The broader literature also points to a need for more extensive long-term safety and efficacy data for newer GLP-2 analogues, which will be crucial for sustained market confidence and adoption. This CHMP opinion, however, firmly establishes glepaglutide as a vital new option, offering hope for improved outcomes and a less burdensome treatment experience for SBS patients across Europe.