FDA Issues CRL to Glepaglutide for Short Bowel Syndrome, Cites Insufficient Evidence

Credit: US Food and Drug Administration

The US Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) to Zealand Pharma’s glepaglutide for the treatment of adult patients with short bowel syndrome (SBS) dependent on parenteral support (PS).¹

Announced on December 19, 2024, the CRL ​​states the New Drug Application (NDA) did not meet the full requirements for substantial evidence to establish the efficacy and safety of the to-be-marketed dose of glepaglutide. As a result, the FDA recommends Zealand Pharma conduct an additional clinical trial to provide further evidence to confirm the efficacy and safety of glepaglutide at the to-be-marketed dose.¹

“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. We remain firm in our belief that glepaglutide provides a significant advance in GLP-2-based therapies for the potential treatment of SBS patients who are dependent on parenteral support,” David Kendall, MD, chief medical officer of Zealand Pharma, said in a press release.¹

According to a press release from Zealand, the company expects to initiate a single phase 3 trial in 2025 that is anticipated to support marketing authorizations for glepaglutide in geographies outside the US and the EU and provide further confirmatory evidence for a regulatory resubmission in the US.¹

A long-acting GLP-2 analog, glepaglutide received orphan drug designation from the FDA on October 24, 2017, based on phase 2 data demonstrating its impact on fecal wet weight output as well as energy, fluid, and electrolyte absorption.² Its NDA was supported by data from the phase 3 EASE program, including 4 clinical trials: EASE-1, EASE-2, EASE-3, and EASE-4.¹

EASE-1 was a randomized, double-blind phase 3 trial that evaluated the safety and efficacy of once- and twice-weekly subcutaneous administration of glepaglutide 10 mg compared with placebo in 106 patients with SBS and intestinal failure who were dependent on PS ≥ 3 days per week. Results showed twice-weekly glepaglutide significantly reduced the total weekly volume of PS at 24 weeks as compared with placebo (P = .0039). While once-weekly glepaglutide also resulted in a numeric reduction in weekly PS, it did not reach statistical significance.³

At 24 weeks, the average reduction in PS 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 PS, while no placebo-treated patients were able to discontinue PS.³

An extension trial of EASE-1, EASE-2 is a randomized, double-blind trial in which SBS patients continued their randomly assigned treatment from EASE-1 with glepaglutide 10 mg once or twice weekly. Patients who received placebo in EASE-1 were re-randomized to treatment with glepaglutide in EASE-2. Results from an interim analysis conducted when all patients had completed ≥ 6 months of treatment showed clinical response to glepaglutide across the key efficacy endpoints was generally maintained or showed continued improvement, including additional patients on both doses weaning off PS.³

Additionally, EASE-3 is evaluating glepaglutide administered once weekly using an auto-injector. Findings from an interim analysisconducted in the first 43 patients rolled over from EASE-2 showed that the reduction in prescribed PS was generally maintained.³

EASE-4 is a phase 3b trial to assess mechanistic effects of glepaglutide on intestinal fluid and energy uptake.³

“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,” Kendall said.¹

References

1. ^{Global News Wire. U.S. Food and Drug Administration issues Complete Response Letter for the glepaglutide New Drug Application for the treatment of short bowel syndrome. December 19, 2024. Accessed December 19, 2024. https://www.globenewswire.com/news-release/2024/12/19/3000220/0/en/U-S-Food-and-Drug-Administration-issues-Complete-Response-Letter-for-the-glepaglutide-New-Drug-Application-for-the-treatment-of-short-bowel-syndrome.html}
2. ^{Biospace. Zealand Pharma submits New Drug Application to the US FDA for glepaglutide in short bowel syndrome. December 22, 2023. Accessed December 19, 2024. https://www.biospace.com/zealand-pharma-submits-new-drug-application-to-the-us-fda-for-glepaglutide-in-short-bowel-syndrome}
3. ^{Biospace. U.S. FDA Grants Orphan Drug Designation To Zealand Pharma’s Glepaglutide for the Treatment of Short Bowel Syndrome. October 24, 2017. Accessed December 19, 2024. https://www.biospace.com/u-s-fda-grants-orphan-drug-designation-to-zealand-pharma-s-glepaglutide-for-the-treatment-of-short-bowel-syndrome}