Regulatory Decision Summary for Tresiba

Benefits

In adult patients with type I diabetes mellitus (T1DM), the efficacy of Tresiba administered once-daily, either with the evening meal or at alternating narrow (8 - 12 hours) and wide (36 - 40 hours) dosing intervals (with injections in the mornings and evenings), and used in combination with a mealtime insulin, was evaluated in three randomized, phase 3, open-label, treat-to-target, active-controlled trials. With respect to change in HbA1c from baseline, and with a non-inferiority margin of 0.4%, treatment with Tresiba for up to 52 weeks was non-inferior to treatment with either insulin glargine or insulin detemir.

In adult patients with T2DM who have failed to achieve glycemic control on common oral anti-diabetic agents (OADs) with or without insulin, or on basal insulin with or without OADs, the efficacy of Tresiba administered once-daily either with the evening meal or at alternating narrow (8 - 12 hours) and wide (36 - 40 hours) dosing intervals (with injections in the mornings and evenings), and used in combination with mealtime insulin and/or in combination with common OADs was evaluated in six randomized, phase 3, open-label, treat-to-target, active-controlled trials. With respect to change in HbA1c from baseline, and with a non-inferiority margin of 0.4%, treatment with Tresiba for up to 52 weeks was non-inferior to treatment with insulin glargine in 5 studies and superior to treatment with sitagliptin in one study.

For patients who miss a dose of Tresiba, the option of administering the missed dose upon discovery (with resumption of the usual dosing schedule, provided at least 8 hours have elapsed between consecutive doses) is considered beneficial and is supported by the phase 3 studies assessing alternating dosing intervals.

Tresiba is provided in two formulations (100 U/mL and 200 U/mL). The option of a higher concentration formulation is a potential benefit for patients requiring high insulin doses, in order to minimize the number of daily injections.

Risks
In the phase 3 trials conducted in T1DM and T2DM patients, the overall safety profile of Tresiba was comparable to insulin glargine and insulin detemir; however, there was a greater frequency and rate of medication errors in subjects exposed to Tresiba compared to those exposed to the comparator.

Interim results for the CVOT outcome trial for Tresiba (known as DEVOTE) were reassuring and met the pre-specified risk margin over the comparator basal insulin. The hazard ratio (Tresiba/insulin glargine) for a composite endpoint of major adverse cardiovascular events (MACE) was 0.920 with a 95% confidence interval upper bound of 1.267.

Conclusion
As compared with basal insulins currently marketed in Canada, the benefit-risk profile of treatment with Tresiba in adult patients with T1DM and T2DM was considered favourable.

As a post-approval commitment, Health Canada has required the final report analysis of the DEVOTE trial to be filed as a supplemental NDS. Several other post-approval safety commitments were required, including the distribution of educational material to help reduce medication error in the Canadian setting.