988-P: MEDI0382, an Oxyntomodulin-Like Peptide with Targeted GLP-1/Glucagon Receptor Activity, Promotes a Dose-Dependent Increase in Gastric Emptying Time

Background: MEDI0382 is an oxyntomodulin-like peptide with targeted GLP-1/glucagon receptor activity under development for type 2 diabetes mellitus (T2DM). GLP-1 and glucagon promote delayed gastric emptying, and GLP-1 tolerance has been described. Methods: This exploratory part of a double-blind phase 2a study measured gastric emptying time (GET) in T2DM patients randomized to daily SC MEDI0382 (n = 20) or placebo (n = 6) for 49 days. Doses were up-titrated fortnightly from 50 to 300 µg. GET was measured after 13 C-octanoate ingestion via serial breath collection with plasma sampling for glucose, insulin, and MEDI0382 C trough levels. GET (t 1/2 = time for 13 C retention to decline 50%; t lag = time when percent excreted 13 C dose peaks) was measured at baseline; 15, 29, 43, 50 days; and 28 days post-dose. Results: GET t 1/2 was significantly prolonged from baseline, by 117.2 min (90% CI 56.2, 178.3) v placebo (-42.9 min; 90% CI -152.0, 66.2; P = 0.039), at 200 µg after 43 days of dosing. Also, at 43 days, t lag was significantly prolonged, by 46.5 min (90% CI, 16.9, 76) v placebo (-27.3 min; 90% CI, -80.0, 25.4; P = 0.048). Numerical increases in t 1/2 and t lag were seen at all dose levels; t lag increased with exposure, as exposure increased with dose up to 200 µg. Lesser delay occurred in GET on day 50 at 300 µg with similar exposure, but alongside significant reduction in glucose AUC of -25.3% (90% CI, -28.2, -22.4; P Discussion: MEDI0382 promoted dose-dependent increase in GET. Although tolerance to this effect may be evident from day 50, reduced postprandial glucose was observed concurrently and may indicate an insulinotropic effect. This unique profile displays characteristics of both short- and long-acting GLP-1 agonism, suggesting that these effects may be mediated by both glucagon and GLP-1 receptor agonism. Disclosure D. Robertson: Employee; Self; AstraZeneca. Employee; Spouse/Partner; GlaxoSmithKline plc. Stock/Shareholder; Self; AstraZeneca. V.E. Parker: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca. P. Ambery: Employee; Self; AstraZeneca. M. Petrone: Employee; Self; MedImmune. T. Wang: Employee; Self; MedImmune. T. Heise: Advisory Panel; Self; Mylan. Research Support; Self; ADOCIA, Boehringer Ingelheim International GmbH, Dance Biopharm Holdings Inc., Eli Lilly and Company, Gan & Lee Pharmaceuticals, Johnson & Johnson, MedImmune, Mylan, Nordic Bioscience, Novo Nordisk A/S, Pfizer Inc., Poxel, Saniona, Sanofi, Wockhardt, Zealand Pharma A/S. Speaker9s Bureau; Self; Eli Lilly and Company, Novo Nordisk A/S. L. Plum-Moerschel: None. L. Jermutus: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. B. Hirshberg: Employee; Self; AstraZeneca. J.J. Meier: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. Funding AstraZeneca