RM-131, a Novel Ghrelin Analog, Demonstrates Potent Prokinetic Activity in Phase 1 Single- and Multiple-dose Studies in Healthy Volunteers

Abstract

Purpose: The unique properties of ghrelin offer great potential to treat clinical conditions associated with impaired gastric motility and energy balance. To date, however, therapeutic candidates that influence ghrelin receptor signaling have made limited progress in clinical evaluation. RM-131 is a novel pentapeptide ghrelin analog that in preclinical studies demonstrated significantly greater potency and advantageous pharmaceutical properties than native ghrelin. We aimed to determine if RM-131 showed similar effects in healthy volunteers. Methods: RM-131 was evaluated in a double-blind, placebo (P)-controlled, single ascending dose (SAD) study at 3 to 2400 μg administered by subcutaneous injection (SC) once daily in nine separate cohorts of four healthy volunteers (3 active/1 P). Endpoints included safety, tolerability and the primary pharmacodynamic (PD) endpoints of gastric emptying (GE) by breath test and expected hormonal response (growth hormone [GH] and prolactin [Pr]). RM-131 was also evaluated in a multiple ascending dose (MAD) study at 10 to 300 μg SC once or twice daily for 14 days in four separate cohorts (8 active/2 P) with similar endpoints. Lower gastrointestinal transit time was also evaluated using the SmartPillTM in a subset of subjects. Results: RM-131 was generally well-tolerated in both studies. Accelerated GE was demonstrated after single and multiple doses of ≥10 μg (35 to 55% change from baseline; p<0.05). PK/PD modeling indicated that the EC50 was <0.5 ng/mL. Results on days 1 and 7 of multiple dosing were similar (Table 1) and suggested that 10 μg was on the plateau of the dose response curve for GE. Potent effects of RM-131 were also demonstrated by dose-dependent increases in circulating levels of GH and Pr the first two hours after dosing on day one. These hormonal responses greatly diminished over time, without evidence of a parallel attenuation in GE response. In the subset of patients in the MAD study evaluated with SmartPillTM, RM-131 treatment was associated with a dose-dependent decrease in colonic transit time (˜50% decrease vs. placebo at 80 μg; p<0.07).Table 1: MAD Study: Gastric emptying time (% change from baseline) by gastric emptying breath testConclusion: RM-131 was generally well-tolerated and produced a clear acceleration of GE in healthy volunteers, even at very low doses. The potent effect on GE in healthy volunteers suggests that this compound holds promise for treatment of disease states characterized by delayed GE (gastroparesis) or otherwise slowed gastrointestinal motility, where effective prokinetic agents may be beneficial. Disclosure: Dr. Kaplan - Scientific Advisor Rhythm Pharmaceuticals. Dr. White - Consultant, Rhythm Pharmaceuticals. Ms. Spence - Consultant, Rhythm Pharmaceuticals. Ms. Kennedy - Consultant, Rhythm Pharmaceuticals. Dr. Stoner - Employee, Rhythm Pharmaceuticals. Dr. Noonan - Consultant, Rhythm Pharmaceuticals. Dr. Laken - Employee, Rhythm Pharmaceuticals. Dr. Gottesdiener - Employee, Rhythm Pharmaceuticals. This research was supported by an industry grant from Rhythm Pharmaceuticals.