Trulicity (dulaglutide): BLA 125469

Dr. Brian T. Hummer has reviewed all of these studies and has recommended approval of the BLA. Please see his review for a detailed discussion of the pharmacology/toxicology program.

Benefits Assessment: The applicant has demonstrated in two adequate and well controlled trials that dulaglutide 0.75 and 1.5 mg administered subcutaneously once weekly result in clinically meaningful improvement glycemic control compared to placebo.

Study GBCF was pre-specified to test the non-inferiority and superiority of dulaglutide 0.75 and 1.5 mg to sitagliptin 100 mg employing a tree-gatekeeping strategy for the multiple objectives tested.

Study GBCF was intended to be a two stage, adaptive, seamless phase 2/3 study that incorporated both dose-finding and demonstration of efficacy and safety.

The primary meta-analysis to evaluate the 1.8 risk margin, as agreed upon with the FDA, estimates the time from randomization to first MACE+ in patients randomized to dulaglutide (pooling all doses) to patients randomized to all comparators (pooling active and placebo controls).

In trial GBCF there was a statistical interaction between baseline HbA1c for both sitagliptin and placebo with the two dulaglutide doses, where comparative reduction in HbA1c was greater in subjects with higher baseline values.

The phase 2 dose-response in efficacy and safety was also supported by the exposure-response relationships which indicated that higher exposure results in larger reduction in HbA1c, fasting plasma glucose, body weight and increase in heart rate (Figure 50, and Figure 7 ).

While this does not permit a clear evaluation for risk of hypoglycemia with this specific background, it is notable that the incidence and event rate in these studies was higher than that seen with the noninsulin/non-insulin secretagogue studies.

We have also determined that a communication plan is necessary to support implementation of the REMS.

The REMS document proposed by the applicant has been revised by DRISK, and recommends the Division of Metabolism and Endocrinology Products send the applicant the comments included in section 8 below.

This will allow physicians to have option of starting at either 0.75 or 1.5 mg after considering benefit-risk profile of dulaglutide.

• Hypoglycemia: When TRULICITY is used with an insulin secretagogue (e.g., a sulfonylurea) or insulin, consider lowering the dose of the sulfonylurea or insulin to reduce the risk of hypoglycemia (5.3).

• TRULICITY has not been studied in patients with a history of pancreatitis [see Warnings and Precautions (5.2)].