The U.S. Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) to Zealand Pharma regarding its New Drug Application (NDA) for glepaglutide, a long-acting GLP-2 analog, intended for treating adult patients with short bowel syndrome (SBS) who are dependent on parenteral support.
The FDA determined that the NDA did not meet the requirements for substantial evidence to establish the efficacy and safety of the to-be-marketed dose of glepaglutide. The agency is recommending that Zealand Pharma conduct an additional clinical trial to provide further evidence to confirm the efficacy and safety of glepaglutide at the proposed dose.
Clinical Trial Data
The NDA submission included data from a single randomized, placebo-controlled Phase 3 registration trial. This trial design is common for rare disease indications like SBS. The trial included two active treatment arms: once-weekly and twice-weekly dosing regimens. The results indicated that twice-weekly treatment with glepaglutide demonstrated significant and superior effects in reducing parenteral support requirements in patients with SBS and intestinal failure (SBS-IF) compared to placebo. However, the once-weekly glepaglutide treatment resulted in a reduction in parenteral support but did not reach statistical significance.
In the EASE-1 trial, a randomized, double-blind Phase 3 study, 106 patients with SBS and intestinal failure, dependent on parenteral support for at least three days per week, were evaluated. Patients were randomized to receive 10 mg of glepaglutide either once or twice weekly, or placebo. The primary endpoint was the absolute change in weekly parenteral support volume from baseline at 24 weeks. The results showed that twice-weekly glepaglutide significantly reduced the total weekly volume of parenteral support at 24 weeks compared with placebo (P = .0039).
At 24 weeks, the average reduction in parenteral support from baseline was 5.13 liters/week for patients treated with glepaglutide twice weekly and 3.13 liters/week for patients treated with glepaglutide once weekly, versus 2.85 liters/week for patients treated with placebo. Among the study participants who were treated with glepaglutide, 9 were completely weaned off parenteral support, while no placebo-treated patients were able to discontinue parenteral support.
Future Plans for Glepaglutide
Zealand Pharma plans to initiate a single Phase 3 trial in 2025 to support marketing authorizations for glepaglutide in geographies outside the U.S. and the EU. This trial is also intended to provide further confirmatory evidence for a regulatory resubmission in the U.S.
"While we are certainly disappointed in the FDA’s decision, we remain confident that the data showed robust and compelling evidence of both efficacy and safety for glepaglutide treatment," said David Kendall, MD, Chief Medical Officer of Zealand Pharma. "We are committed to working with the agency to align on the path toward a regulatory approval, so that we can bring glepaglutide to patients in the U.S. In parallel, we expect to proceed with our current plans for a European Marketing Authorization Application submission in 2025."
About Glepaglutide
Glepaglutide is a long-acting GLP-2 analog in development as a potential treatment option for short bowel syndrome (SBS). It is being developed as a liquid product in an autoinjector designed for subcutaneous administration, aimed to reduce or eliminate the need for parenteral support in people living with SBS. The FDA has granted orphan drug designation for glepaglutide for the treatment of SBS.
The Phase 3 program, named EASE, includes four clinical trials evaluating the potential for glepaglutide to reduce or eliminate the need for parenteral support in SBS patients with intestinal failure. These trials include EASE-1, EASE-2, EASE-3, and EASE-4.
