Zepbound (tirzepatide): NDA 217806

Dr. Carver reviewed and recommends approval of the final carton and container labeling, agreed upon with the Applicant.

In summary, Dr. Carver and the individual discipline reviewers all support approval of the application, and I concur with their recommendations.

The Office of Pharmaceutical Quality (OPQ) recommends approval, including approval for all facilities listed in the application.

The FDA clinical pharmacology review team recommends approval, and I concur with the recommendation.

Both Dr. Soccio and Dr. Song recommend approval of tirzepatide as an adjunct to a reducedcalorie diet and increased physical activity for chronic weight management in the proposed population.

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

This application provides substantial evidence of effectiveness that tirzepatide injection, administered subcutaneously once weekly, results in clinically meaningful weight loss and improvement in anthropometric and cardiometabolic parameters in patients with obesity or overweight.

For substantial evidence of effectiveness for the indication of CWM, the Division considers the primary endpoint of placebo-corrected mean percent change in body weight from baseline in the intention-to-treat population after at least one year on the maintenance dosage.

There are some statistically significant treatment-by-subgroup interactions in the table above (sex, ethnicity, and BMI category in GPHK and HbA1c category in GPHL), which the Applicant states have no obvious clinical relevance.

Change from baseline in SF-36v2 Physical Functioning Domain Score was a multiplicity-controlled key secondary endpoint in trial GPHK (comparing the pooled 10 mg and 15 mg weekly dosages to placebo), while this was a secondary endpoint in trial GPHL, and all other PRO-related endpoints were secondary or exploratory.

Across populations in the two phase 3 CWM trials, >79% and up to 90.9% of tirzepatidetreated trial subjects achieved >=5% weight loss, a threshold the Division has considered for clinical meaningfulness (compared to 32.5-34.5% of placebo-treated subjects).

Of note, the placebo group in the DXA substudy had higher body weights, BMI, and waist circumference than the tirzepatide 5 mg group, though the 10 mg and 15 mg groups were more similar to placebo.

Conduct a medullary thyroid carcinoma registry-based case series of at least 15 years duration to systematically monitor the annual incidence of medullary thyroid carcinoma in the United States and to identify any increase related to the introduction of Zepbound (tirzepatide) for the treatment of overweight and obesity into the marketplace.

Serum calcitonin concentrations were monitored during trials GPHK and GPHL to assess whether tirzepatide affects C-cell function, potentially indicating the development of C-cell hyperplasia or MTC.

Hypersensitivity is generally included in Section 5 (Warnings and Precaution) of labeling for other incretin drugs, with a Section 4 contraindication for individuals with a history of a serious hypersensitivity reaction to the respective incretin drugs.

Most AEs were cutaneous, few clearly indicated systemic hypersensitivity reactions, and none were serious.

Section 5 (Warning and Precautions) of labeling will include a subsection on "Hypoglycemia," describing the risks in patients with and without T2D.

Reviewer comment: The final Section 6.1 of labeling will describe the incidences of hypoglycemia in subjects without T2D in trial GPHK under "Other Adverse Reactions".

Dr. Sheikh supports approval of the application from an immunogenicity perspective and concluded that a PMC is not required for this application.

FDA will issue postmarketing requirements for pediatric studies with the approval of this application.

Below in bold are the 6 postmarketing requirements (PMRs) that will be issued for tirzepatide; no postmarketing commitments (PMCs) are recommended for this application.

The final PK protocol I8F-MC-GPHV was submitted, so there is no protocol submission milestone for this PMR.

Below in bold are the two postmarketing requirements (PMRs) that will be issued for tirzepatide; no postmarketing commitments (PMCs) are recommended for this application.