Senior Research Director, MedImmune
MEDI0382, a Novel Dual GLP1/Glucagon Receptor Agonist, from Bench to Bedside
Introduction: Despite a wide range of therapies for patients with type 2 diabetes and obesity,
only intensive dietary and lifestyle interventions or bariatric surgery provide substantial weightloss to reduce insulin resistance and improve glycemic control. Improvements in glucose
metabolism after surgery precede weight loss and are associated with alterations in circulating
levels of gut hormones, including oxyntomodulin and glucagon-like peptide-1 (GLP-1).
MEDI0382, a single peptide with GLP-1 and glucagon (GCG) receptor dual-agonist activity, is
designed to mimic the effects of oxyntomodulin. Results from preclinical studies and the firsttime-
in-humans (FTIH) study are presented.
Objectives: 1. To characterize the pharmacology of MEDI0382 in animal models of obesity and
diabetes. 2. To assess the safety and tolerability of single ascending doses of MEDI0382 in
Methods: The potency of peptide analogs was determined in cyclic AMP accumulation assays
performed in CHO cells stably expressing GLP-1 or GCG receptors. The ability of MEDI0382 to
reduce body weight and control blood glucose was evaluated in mouse models of obesity and
diabetes and in healthy cynomolgus monkeys after single and repeated daily subcutaneous
administration for up to 2 months. A FTIH, double-blind, placebo-controlled study assessed
safety and tolerability. The phase 1 study randomized (3:1) 8 healthy subjects (per cohort; total
n = 48) aged 18–45 years to single doses of MEDI0382 (5, 10, 30, 100, 150, and 300 μg) or
placebo, respectively. Subjects received investigational product subcutaneously on day 1 after
≥8 hours of fasting. Data were collected until Day 28.
Results: MEDI0382 potently activated rodent, monkey, and human GLP-1 and GCG receptors
and exhibited a 5-fold bias for activation of GLP-1 receptor versus the GCG receptor. In dietinduced
obese (DIO) mice, 21 days of MEDI0382 (10 or 30 nmol/kg QD) reduced body weight by
24.5% and 32.5%, respectively, compared with controls. The effect was superior to that of
liraglutide (40 nmol/kg QD), although liraglutide had a greater effect on inhibiting food intake
than MEDI0382, suggesting that MEDI0382 may increase energy expenditure. Relative to pairfed
mice, MEDI0382 administration (10 nmol/kg QD) further enhanced body weight loss after
10 days of dosing and significantly increased metabolic rate when assessed at days 17‒20.
Substrate utilization was also reduced, indicating preferential oxidation of fat. Together,
enhanced metabolism and lipid oxidation may contribute to the mechanism by which
MEDI0382 reduces body weight. Glucose tolerance was significantly improved in MEDI0382-.