FDA Issues Complete Response Letter for Much-Anticipated GLP-2 Analog

FDA officials issued a complete response letter to Zealand Pharma A/S, the company developing the long-acting glucagon-like peptide-2 (GLP-2) analog glepaglutide for adults with short bowel syndrome (SBS) with intestinal failure who are dependent on parenteral support.¹

The complete response letter states that the new drug application is not ready for approval in its current form. According to a news release, FDA officials have recommended an additional clinical trial to confirm the efficacy and safety of glepaglutide at the anticipated dose for marketing.¹

FDA sign | Image credit: Tada Images | stock.adobe.com

“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,” David Kendall, MD, chief medical officer at Zealand Pharma, said in the news release. “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.”¹

SBS develops when the small intestine is shortened or damaged, meaning it is unable to absorb enough nutrients from foods. This results in symptoms such as diarrhea, fatigue, and weight loss. It is most common in individuals who have undergone small bowel resection.²

Treatments for SBS include nutritional support, fluids and electrolytes, surgery, and pharmacological options. The primary goals of treatment are to ensure the patient gets enough nutrients, prevent complications, and reduce the need for parenteral nutrition. In patients who require it, however, parenteral nutrition prevents malnutrition and has been shown to improve patient outcomes. However, complications can include infected administration sites or cannulated vein thromboses.³

Glepaglutide is a long-acting GLP-2 analog being developed in an autoinjector for subcutaneous administration. The goal of the treatment is to reduce or eliminate the need for parenteral support in patients with SCS. The phase 3 EASE program includes 4 clinical trials evaluating the potential for glepaglutide for this patient population.¹

EASE-1 enrolled 106 patients with SCS with intestinal failure who were dependent on parenteral support for at least 3 days per week. Participants were randomized to receive treatment with 10 mg glepaglutide either once or twice weekly or placebo. The primary end point was absolute change in weekly parenteral support volume from baseline at 24 weeks.¹

Of the 106 participants, 102 completed EASE-1, 96 of whom continued into the ongoing 2-year, long-term safety and efficacy expansion trial, EASE-2. In this trial, patients continued their assigned treatment from EASE-1, and patients who originally received the placebo were re-randomized to treatment with glepaglutide 10 mg once or twice weekly. Patients who complete EASE-2 are eligible to participate in EASE-3, evaluating glepaglutide administered once weekly with an autoinjector. EASE-4 is a phase 3b trial to assess long-term effects of glepaglutide on intestinal fluid and energy uptake.¹

REFERENCES

1. US Food and Drug Administration issues complete response letter for the glepaglutide new drug application for the treatment of short bowel syndrome. News release. Zealand Pharma. December 19, 2024. Accessed December 20, 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. Short Bowel Syndrome. National Institute of Diabetes and Digestive and Kidney Diseases. Accessed December 20, 2024. https://www.niddk.nih.gov/health-information/digestive-diseases/short-bowel-syndrome

3. Short-Bowel Syndrome Treatment & Management. Medscape. Updated August 27, 2024. Accessed December 20, 2024. https://emedicine.medscape.com/article/193391-treatment