Ambery P, et al. - This randomized, placebo-controlled, double-blind, combined multiple-ascending dose (MAD) and phase 2a study evaluated the efficacy, tolerability, and safety of treatment with MEDI0382 (a balanced glucagon-like peptide-1 and glucagon receptor dual agonist developed to provide glycemic control and weight loss) in type 2 diabetic patients. Findings revealed that in obese or overweight individuals with type 2 diabetes, MEDI0382 has the potential to provide clinically meaningful reductions in blood glucose and bodyweight.

Methods

• This investigation was conducted at 11 study sites (hospitals and contract research organizations) in Germany.
• Study participants were patients aged 18-65 years with controlled type 2 diabetes (glycated hemoglobin A_1c[HbA_1c] levels of 6·5–8·5% at screening) and a body-mass index between 27 kg/m² and 40 kg/m².
• Researchers used an interactive web-response system to randomize patients to receive MEDI0382 or placebo.
• For this analysis, patients were randomized 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.
• They performed randomization 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 evaluation members were masked to treatment allocation.
• Subjects received once-daily subcutaneous injections of the study drug at doses of no more than 300 μg for 22 days or less in the MAD portion of the study, and a dose of no more than 200 μg for 41 days or less in the phase 2a portion.
• After that, 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_{0–4 h}) after a mixed-meal tolerance test (MMTT), evaluated in all members 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, evaluated in the intention-to-treat (ITT) population.
• According to the treatment they received, safety analyses were done in all participants who received any study drug analyzed.

Results

• Between December 9, 2015, and February 24, 2017, patients were enrolled.
• Sixty-one subjects were randomly assigned to the MAD part of the study (42 to MEDI0382 and 19 to placebo) and 51 subjects were randomly assigned to the phase 2a part, of whom 25 were randomized to MEDI0382 and 26 to placebo.
• In the phase 2a study, three subjects in the MEDI0382 group and one in the placebo group discontinued, all because of adverse events.
• It was observed that 22 (88%) subjects 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.
• It was noted that glucose AUC_{0–4 h} post MMTT decreased significantly with MEDI0382 vs placebo (least squares [LS] mean -32·78% [90% CI -36·98 to -28·57] vs -10·16% [-14·10 to -6·21], and the mean difference was -22·62% [-28·40 to -16·85]; p < 0·0001).
• Findings revealed that in the ITT population, reduction in bodyweight was significantly greater with MEDI0382 than with placebo (LS mean -3·84 kg [90% CI -4·55 to -3·12] vs-1·70 kg [-2·40 to -1·01] and mean difference of 2·14 kg [-3·13 to -1·31]; p=0·0008).
• It was found that the percentage of patients who had a treatment-emergent adverse events (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.
• According to the findings obtained, no participants in the MEDI0382 group had a grade 3 or worse TEAE (vs two [8%] in the placebo group).