MEDI0382, a GLP-1 and glucagon receptor dual agonist, in obese or overweight patients with type 2 diabetes: a randomised, controlled, double-blind, ascending dose and phase 2a study

Background Weight loss is often key in the management of obese or overweight patients with type 2 diabetes, yet few treatments for diabetes achieve clinically meaningful weight loss. We aimed to assess the efficacy, tolerability, and safety of treatment with MEDI0382, a balanced glucagon-like peptide-1 and glucagon receptor dual agonist developed to provide glycaemic control and weight loss, in patients with type 2 diabetes. Methods This randomised, placebo-controlled, double-blind, combined multiple-ascending dose (MAD) and phase 2a study was done at 11 study sites (hospitals and contract research organisations) in Germany. We enrolled patients aged 18-65 years with controlled type 2 diabetes (glycated haemoglobin A(1c) [HbA(1c)] levels of 6 center dot 5-8 center dot 5% at screening) and a body-mass index between 27 kg/m(2) and 40 kg/m(2). An interactive web-response system was used to randomly assign patients to receive MEDI0382 or placebo. Patients were randomly assigned 2: 1 in cohorts A-C and 3: 1 in cohorts D and E in the MAD portion of the study, and 1: 1 in the phase 2a portion. Randomisation was done by a contracted third- party operator who was not involved in the clinical operations of the study. The pharmacists, participants, and study site personnel involved in treating and assessing participants were masked to treatment allocation. Patients received once-daily subcutaneous injections of the study drug at doses of no more than 300 mu g for 22 days or less in the MAD portion of the study, and a dose of no more than 200 mu g for 41 days or less in the phase 2a portion. The two primary endpoints of the phase 2a portion were the change from baseline to day 41 in glucose area under the curve at 0-4 h (AUC(0-4h)) after a mixed-meal tolerance test (MMTT), assessed in all participants who received at least one dose of study drug and whose measurements were taken at baseline and day 41, and change from baseline in bodyweight, assessed in the intention-to-treat (ITT) population. Safety analyses were done in all participants who received any study drug analysed according to the treatment they received. This study is registered with ClinicalTrials. gov, number NCT02548585. Findings Patients were recruited between Dec 9, 2015, and Feb 24, 2017. 61 patients were randomly assigned to the MAD part of the study (42 to MEDI0382 and 19 to placebo). 51 patients were randomly assigned to the phase 2a part, of whom 25 were randomly assigned to MEDI0382 and 26 to placebo. In the phase 2a study, three patients in the MEDI0382 group and one in the placebo group discontinued, all as a result of adverse events. 22 (88%) patients in the MEDI0382 group and 25 (96%) in the placebo group received at least one dose and had measurements taken at baseline and day 41. Glucose AUC(0-4h) post MMTT decreased significantly with MEDI0382 versus placebo (least squares [LS] mean -32 center dot 78% [90% CI-36 center dot 98 to-28 center dot 57] vs-10 center dot 16% [-14 center dot 10 to -6 center dot 21], and the mean difference was -22 center dot 62% [-28 center dot 40 to -16 center dot 85]; p<0 center dot 0001). In the ITT population, reduction in bodyweight was significantly greater with MEDI0382 than with placebo (LS mean -3 center dot 84 kg [90% CI -4 center dot 55 to -3 center dot 12] vs - 1 center dot 70 kg [- 2 center dot 40 to - 1 center dot 01] and mean difference of 2 center dot 14 kg [- 3 center dot 13 to - 1 center dot 31]; p=0 center dot 0008). The proportion of patients who had a treatment-emergent adverse event (TEAE) was similar between treatment groups (22 [88%] of 25 in the MEDI0382 group vs 23 [88%] of 26 in the placebo group); gastrointestinal disorders (18 [72%] vs 13 [40%]) and decreased appetite (five [20%] vs none) occurred more frequently with MEDI0382 than placebo. No participants in the MEDI0382 group had a grade 3 or worse TEAE (vs two [8%] in the placebo group). Interpretation MEDI0382 has the potential to deliver clinically meaningful reductions in blood glucose and bodyweight in obese or overweight individuals with type 2 diabetes.