CHICAGO – The investigational ghrelin agonist RM-131 significantly improved gastric emptying and vomiting in patients with diabetic gastroparesis in a phase II, double-blind study.
Gastric emptying improved by an average of 23 minutes from baseline after 4 weeks of twice-daily subcutaneous injections of RM-131 10 mcg (P less than .001). This compares with nonsignificant improvements of 7.5 minutes for placebo and 5.9 minutes for once-daily RM-131 10 mcg, Dr. Anthony Lembo reported in a late-breaking abstract session at the annual Digestive Disease Week.
Twice-daily RM-131 also reduced weekly vomiting episodes by 63% (P = .033) and vomiting severity by 58% (P = .005), compared with placebo.
Patrice Wendling/Frontline Medical News
Dr. Anthony Lembo
RM-131, also known as relamorelin, has been granted fast-track review status by the Food and Drug Administration for the treatment of diabetic gastroparesis. The novel ghrelin pentapeptide agonist is 15- to 130-fold more potent than ghrelin, a hormone produced in the stomach that stimulates gastrointestinal activity, according to Dr. Lembo, with Beth Israel Deaconess Medical Center in Boston.
The study enrolled 204 patients with type 1 or type 2 diabetes and a hemoglobin A1c value of less than 11%; a history of ongoing gastroparesis symptoms; nausea and/or vomiting at least once in the 2 weeks prior to enrollment; and a screening gastric emptying time of more than 79 minutes. Their mean age was 55 years.
A post hoc analysis on patients with baseline vomiting showed that twice-daily RM-131 was effective on all endpoints, including four subjective patient-reported symptoms – nausea, abdominal pain, bloating, and early satiety, Dr. Lembo said.
Gastric emptying, as demonstrated by the Gastric Emptying Breath Test, improved by 30.6 minutes from baseline (P = .02), weekly vomiting episodes by 63% (P = .041), and vomiting severity by 59% (P = .006).
The four-symptom composite score improved numerically, but not significantly, in the overall population, whereas there was a clear and significant improvement in 1 week in the subgroup with vomiting (6.36 points; P less than .043), he said.
The subgroup with vomiting comprised about 60% of the study population, and had 5.6 to 6.4 baseline vomiting episodes per week versus 3.2 to 3.5 per week in the overall population. Vomiting is the most bothersome symptom in diabetic gastroparesis and often brings patients to the hospital for treatment, Dr. Lembo observed.
The subset with vomiting also had more severe overall gastric emptying symptoms at baseline. Initial analyses, however, suggest a weak correlation between improvement in gastric emptying and symptom improvement, he said.
Session cochair Dr. John Inadomi, professor of medicine and head of gastroenterology, University of Washington, Seattle, said in an interview that the weak correlation "is not surprising given what we know about gastroparesis and the pathogenesis of symptoms, but it does raise questions about where the most effective therapy is going to come from. Is it going to come from trying to accelerate gastric emptying or trying to go after some other way to relieve symptoms? Nevertheless, this is the first study of a so-called pure prokinetic that has had at least some clinical benefit, but again, it was in the subset of patients with vomiting."
Treatment-emergent adverse events occurred in 30 of 69 patients (43.5%) on placebo, 32 of 67 patients (47.8%) on once-daily RM-131, and 25 of 68 patients (36.8%) on twice-daily dosing. No adverse event was more common with RM-131 and likewise, there were no concerns about labs, glucose, weight, ECGs, physical exam, or injection-site reactions, Dr. Lembo said.
Rhythm Pharmaceuticals sponsored the study. Dr. Lembo reported relationships with Salix Pharmaceuticals, AstraZeneca, and other companies. Dr. Inadomi reported relationships with Given Imaging, ChemImage, and other companies.