Mounjaro (tirzepatide): NDA 215866

The benefit risk profile is favorable and supports FDA approval of tirzepatide for the proposed indication "as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus".

The OCP/DCEP determined that the clinical pharmacology data submitted to this NDA were acceptable, and recommended approval from a clinical pharmacology perspective.

Five Phase 3 trials met the criteria for adequate and well-controlled studies (21 CFR 314.126) and support approval of tirzepatide, demonstrating substantial evidence of effectiveness.

Reviewer Comment: I conclude that the Applicant has provided the substantial evidence of effectiveness required by law [see 21 CFR 314.126(a)(b)] to support approval.

In accordance with 21CFR314.126, the Applicant has provided substantial evidence of effectiveness for the proposed indication as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

The efficacy of tirzepatide was compared to placebo (trial GPGK as monotherapy and trial GPGI as add-on to insulin glargine), insulin glargine as add-on to metformin and/or a SU and/or a SGLT2i (trial GPGM), insulin degludec as add-on to metformin with or without a SGLT2i (trial GPGH), and semaglutide 1 mg (trial GPGL) as add-on to metformin.

The efficacy of tirzepatide was compared to placebo (trials GPGI and GPGK), insulin glargine (trial GPGM), insulin degludec (trial GPGH), and semaglutide 1 mg (trial GPGL).

• Trial 18F-MC-GPGK (SURPASS-1): A multicenter, randomized, double-blind, parallel-group, placebo-controlled, phase 3 trial in subjects with T2D, naive to antihyperglycemic injectable therapy, inadequately controlled with diet and exercise alone, and had not been treated with any oral antihyperglycemic medication during the three months preceding to the start of the trial.

Although he noted that tirzepatide was highly immunogenic, he felt that no safety or efficacy concern(s) were correlated with ADA development in subjects participating in the clinical studies conducted under this NDA. From an immunogenicity perspective, he recommended approval of tirzepatide.

The Applicant felt that there was no evidence of increased risk of MTC, C-cell hyperplasia, or persistently elevated calcitonin levels with the use of tirzepatide, and therefore they did not recommend routine monitoring of serum calcitonin or thyroid ultrasound in patients receiving tirzepatide.

For this review, immediate and non-immediate hypersensitivity AEs were combined to evaluate the overall risk of hypersensitivity reactions associated with the use of tirzepatide.

In conclusion, no additional risk evaluation and mitigation strategy is recommended for this product.

Therefore, Lilly has not proposed a Risk Evaluation and Mitigation Strategy."

This review by the Division of Risk Management (DRM) evaluates whether a risk evaluation and mitigation strategy (REMS) for the new molecular entity Mounjaro (tirzepatide) is necessary to ensure the benefits outweigh its risks.