Pharmacodynamic effects of ghrelin agonist RM-131 in patients with type 1 and type 2 diabetes mellitus and prior documentation of delayed gastric emptying

Background: There is a need for effective pharmacologic therapies for diabetic gastroparesis. RM-131, a novel synthetic ghrelin agonist, is effective in reversing ileus in animals. Aim: To investigate pharmacodynamics (PD) of a single dose of RM-131 in type 1 (T1DM) and type 2 (T2DM) diabetes mellitus patients with prior documentation of delayed gastric emptying (DGE). Methods: A randomized, placebo-controlled, crossover study was conducted T1DM and T2DM patients with prior documentation of DGE. Patients received one subcutaneous injection of RM-131 or placebo then crossed-over to alternative therapy after a 7-day wash-out. Scintigraphic gastric emptying (GE) and colonic filling at 6h (CF6) of a solid-liquid meal were assessed. Symptoms were assessed using a daily diary gastrointestinal cardinal symptom index (GCSI-DD) after both treatments. Pharmacokinetics (PK) was assessed in T2DM and compared to a previously developed Emax PK/PD model in healthy volunteers (HV) for GE T1/2. Results: RM-131 accelerated GE T1/2 solids compared to placebo; mean difference (p=0.01) was 68.3 minutes [95%CI 20-117] or 66.1% in T2DM; median difference (p=ns) was 33.9 minutes (IQR -12, -49); or -54.7% in T1DM. RM-131 increased solid GE at 1 (p<0.01) and 2 hours (p=0.02) in T1DM. There were numerical differences in GE lag, CF6 solids, and liquid GE T1/2 in both groups. PK was similar in T2DM patients and HV. Total GCSI-DD scores were lower on RM-131 (p=0. 0.03) in T1DM. Conclusions: RM-131 significantly accelerates solid GE in T1DM and T2DM patients with DGE which has previously not been observed with other ghrelin agonists. These findings will serve as the basis for future clinical investigations of this novel compound.