Xultophy 100/3.6 (insulin degludec; liraglutide): BLA 208583

The Office of Clinical Pharmacology review team has recommended approval of IDegLira.

Dr. Condarco (Clinical) and Anna Kettermann (Statistical) recommend approval of IDegLira.

Dr. Cooke also felt that IDegLira should be approved for all the populations that were studied.

DRISK agrees with all the changes proposed by the applicant in this amendment and recommends approval of the REMS.

FDA also expressed concern that subjects receiving less than the minimum established clinically effective dose (i.e., <1.2 mg) of liraglutide would not be expected to derive any clinical benefit from the liraglutide in the combination but would be potentially exposed to risks associated with liraglutide use.

Three trials were openlabeled (3697, 3851, and 3952); two trials, one pivotal trial, (3912) and a placebo controlled trial, (3951) were double-blinded trials in which visually identical cartons and pen devices for investigational drug products were used.

However, the clinical implications of the rapidity in achievement of the target HbA1c level remains an area of uncertainty in diabetes management, and the clinical benefit of sequential vs. initial dual/triple therapy is unclear.

The Sponsor has provided substantial evidence of effectiveness to support approval of IDegLira in patients previously treated with insulin.

The Victoza label specifies glycemic benefits are observed at doses greater than 1.2 mg. Therefore, there are concerns regarding the clinical benefits of using IDegLira doses with a liraglutide component below 0.6 mg (the starting dose of liraglutide).

The Sponsor submitted 5 new phase 3 studies in T2DM as evidence of efficacy: 2 pivotal trials (3697 and 3912) and 3 other supportive studies that evaluated IDegLira in other T2DM populations (3851, 3951, and 3952).

• Revise Warnings and Precautions Section 5.2 Acute Pancreatitis for consistency with the class.

FDA expressed concern that no data will be obtained in the currently proposed IDegLira program to inform prescribers on IDegLira's risk-benefit profile in these other settings.

In general, the findings from the IDegLira program suggest that IDegLira is associated with severe and/or serious hypoglycemia, which is higher than that of placebo- as in trial 3951 (when either is combined with OADs including sulfonylureas).

On May 11, 2016 the Sponsor was asked to revise the proposed REMS document and the REMS supporting document to align with the Saxenda REMS and to reflect the FDA's current thinking about the description of relevant elements of the communication plan.

This is a review of the Novo Nordisk proposed risk evaluation and mitigation strategy (REMS) amendment for Xultophy 100/3.6 (insulin degludec and liraglutide injection) (NDA 208583) received November 15, 2016. This review evaluates the amendment to the Xultophy REMS due to proprietary name change from Xultophy to Xultophy 100/3.6, and change of indication.

Consistent with prior FDA regulatory actions for liraglutide products, DRISK and the Division of Metabolism and Endocrinology Products agree that a CP REMS is needed to ensure that the benefits of Xultophy outweigh it risk of thyroid C-cell tumor.