Regulatory Decision Summary for Bydureon

Exenatide QW (Bydureon), metformin (Glucophage), and basal insulin glargine (Lantus) are all antihyperglycemic medications for adults with type 2 diabetes mellitus (T2DM). In the current Canadian clinical treatment paradigm, patients with T2DM are first treated with metformin and if they are inadequately controlled on metformin, additional therapeutic options are prescribed to control blood glucose levels, as measured by haemoglobin A1C (HbA1c) levels. Bydureon is one of many therapeutic options that can be added to metformin to improve glycemic control in T2DM.

The current application is to provide information on the efficacy and safety of Bydureon as add-on treatment to titrated basal insulin with or without metformin. This proposed change is being supported by Study D5553C00002: a 28-week, multicenter, randomized, double-blind, placebo-controlled, parallel group, Phase 3 trial to evaluate the safety and efficacy of exenatide QW therapy added to titrated basal insulin glargine compared to placebo added to titrated basal insulin glargine in patients with T2DM who have inadequate glycemic control on basal insulin glargine with or without metformin.

In total, 464 subjects were randomized into Study D5553C00002: 233 patients were randomized to Bydureon and 231 patients were randomized to placebo. The primary efficacy endpoint was reduction in glycated HbA1c compared to placebo on a background of titrated insulin glargine (with or without metformin). The results of Study D5553C00002 showed a statistically significant and clinically meaningful reduction from baseline HbA1c when compared to placebo. The mean change in HbA1c was -0.96% for Bydureon and -0.23% for the placebo. The difference in mean change between the Bydureon and the placebo was -0.73% (p<0.001). Other efficacy endpoints (i.e. reduction in body weight, reduction in 2-hour postprandial glucose, fasting plasma glucose and the proportion of subjects achieving HbA1c <7%) were consistent with, and supportive of, the result of the primary efficacy endpoint.

The adverse reactions that most commonly resulted in discontinuation were gastrointestinal disorders. These are known side-effects with exenatide. Overall, no important new or synergistic adverse reaction was observed in the trial.

A major uncertainty with the current application was the proposed change to dosing and administration to allow the patient to shift the day of weekly exenatide administration. The submitted pharmacokinetic Study 2993LAR103 does not support the safety of the proposed change for shift in the day of weekly dosing, as the dose modification analysis in Study 2993LAR103 was a simulation study using a dose (10 mg) that is not the approved recommended dose of 2 mg/week and the simulation does not provide safety information to support such a shift.

A second uncertainty was the lack of data in patients aged 75 years and older. This is a vulnerable patient subset; however, the current approved Product Monograph contains a cautionary statement on use in patients >75 years of age.

Risk mitigation was achieved with adequate labelling of all safety issues and retention of the currently approved wording for dose adjustment. The overall benefit-harm-uncertainty profile of Bydureon is considered favourable for the indication of co-administration with basal insulin (alone or with metformin).