By David Douglas
NEW YORK (Reuters Health) - 29/3/2019
The novel long-acting glucagon-like peptide-2 analogue glepaglutide appears to improve intestinal function in patients with short-bowel syndrome, according to a small randomized trial.
As Dr. Rahim Naimi told Reuters Health by email, "Treatment with 1 mg and 10 mg glepaglutide resulted in a significant and clinically meaningful reduction in fecal output in patients with short-bowel syndrome."
In the new study, a phase 2 trial with crossover design, Dr. Naimi of Rigshospitalet, in Copenhagen, and colleagues randomized 18 patients with a fecal wet-weight output of 1,500 g/day or more to receive one of six dose sequences of glepaglutide (10 mg, 1 mg; 10 mg, 0.1 mg; 1 mg, 10 mg; 1 mg, 0.1 mg; 0.1 mg, 10 mg; or 0.1 mg, 1 mg). They analyzed results from the 16 patients who completed the study.
Each patient was given daily subcutaneous injections of the first assigned dose of glepaglutide for three weeks, followed by a washout period of four to eight weeks, and then the second dose.
No changes were seen with the 0.1 mg dosage, but treatment with 1 mg reduced the mean adjusted fecal output from baseline by 592 g/day, the team reports in The Lancet Gastroenterology & Hepatology, online March 14. With 10 mg the reduction was 833 g/day. There were corresponding improvements in intestinal wet-weight absorption.
All patients had at least one drug-related adverse event, but according to the researchers "most were mild or moderate." The most common adverse events were stoma complications in 13 patients, transient injection-site reactions in 11 and fatigue in six. These were more frequent with increasing dose.
There were seven serious adverse events in two patients during treatment with 0.1 mg and three serious adverse events in two patients during treatment with 10 mg. These included abdominal pain, catheter-related sepsis and infection of unknown origin. None was reported during treatment with the 1 mg dose.
The researchers note that the daily dosing regimen used in this trial was based on results from an earlier phase 1 trial, in which incomplete pharmacokinetic findings suggested a shorter half-life of the agent than is the case.
In fact, concluded Dr. Naimi, with a "long half-life of approximately 50 hours, and the potential for once weekly administration, glepaglutide is a promising potential treatment option for these often under-diagnosed and undertreated patients."
A phase 3 trial to further confirm and assess the efficacy and safety of the agent is underway. It aims to enroll 129 patients at approximately 40 sites across the United States, Canada and Europe. So far, 12 patients have been randomized and treated.
Dr. Tim Vanuytsel, author of an accompanying editorial, told Reuters Health by email that the researchers "are at the forefront of the research on GLP-2 analogues in short-bowel syndrome. In this phase 2 study they demonstrated improved intestinal absorption with daily administration of glepaglutide, a novel GLP-2 analogue with a longer half-life compared to teduglutide."
Teduglutide, a GLP-2 analogue, was approved in Europe and the U.S. in 2012 for long-term treatment of patients with short-bowel syndrome. "The advent of novel molecules like glepaglutide and others, which are in the pipeline, open the perspective of less than daily injections to reduce parenteral support needs and improve quality of life in short-bowel syndrome patients," added Dr. Vanuytsel of the University of Leuven, in Belgium.
The study was funded by Zealand Pharma, the developer of glepaglutide. Dr. Naimi has been an employee of the company and three of the authors are currently employees.
Lancet Gastroenterol Hepatol 2019.