Zealand Pharma US, Inc. – FDA CRL

Zealand Pharma US, Inc. received a Complete Response Letter from the U.S. Food and Drug Administration (FDA) for its New Drug Application (NDA 218828) for glepaglutide injection, proposed to treat short bowel syndrome (SBS). The FDA determined it could not approve the application in its current form, citing a lack of substantial evidence of effectiveness and concerns that the benefits do not outweigh the known and anticipated risks. The FDA's review identified significant deficiencies with the clinical data, particularly from the single Phase 3 trial, EASE-1. Key issues included numerous protocol deviations in parenteral support (PS) volume adjustments and widespread incomplete documentation of critical data like urinary output, which undermined the reliability of efficacy assessments. A misconfigured eDiary for PS volume values further compounded data integrity concerns. Qualitative data from exit interviews and anchor-based analyses using Patient Global Impression of Change were deemed inadequate to establish clinically meaningful changes. Furthermore, a significant percentage of patients experienced substantial body weight loss, raising questions about the clinical benefit of observed PS reductions. Inconsistencies in dose-response between EASE-1 and EASE-2 trials, coupled with a lack of exposure-response relationship, led to uncertainty regarding the appropriateness and effectiveness of the proposed glepaglutide dosage. To achieve approval, Zealand Pharma US, Inc. must address these deficiencies by providing more robust and interpretable data to demonstrate the efficacy and safety of glepaglutide for SBS patients.