Imcivree (setmelanotide acetate): NDA 213793

Testing and validation to support approval of the device application will be the subject of a post marketing commitment (PMC).

This reviewer recommends that, if setmelanotide is approved, a REMS is not needed to ensure its benefits outweigh its risks.

The Applicant has provided substantial evidence of effectiveness to support approval for chronic weight management in patients with POMC, PCSK1, or LEPR deficiency obesity in adults and children 6 years of age and older.

Reproductive toxicity studies in rats and rabbits demonstrated no adverse effects up to the highest dose of 5 mg/kg/day (11-times the MRHD), despite expected, dose-related reductions in maternal food consumption and body weight gain.

Key secondary efficacy endpoints were analyzed in the DUS population (percent change from baseline in body weight, "most hunger in the past 24-hours"), and in the FAS population (categorical analysis for a threshold of >=25% improvement in hunger scores).

The primary endpoint relied on absolute weight values, however in pediatric subjects who continue to grow, a BMI based metric may be better in order to assess clinical benefit.

In Study 012, one subject was labeled as discontinued the study due to lack of efficacy.

Changes in weekly average 'most hunger' score were also compared between treatments during the 8-week placebo-controlled withdrawal period: In Study 012 the mean score was 4.9 during treatment with setmelanotide and 7.1 during treatment with placebo.

Of the 27 subjects in the safety database, based on the original data cutoff date, there were 3 (11%) subjects that had at least one episode of depression and 3 (11%) subjects that had suicidal ideation.

No Postmarketing Risk Evaluation and Mitigation Strategies (REMS) are required for approval of this application.

The Division of Risk Management (DRM) and the Division of Diabetes, Lipid disorders, and Obesity (DDLO) agree that a REMS is not needed to ensure the benefits of setmelanotide outweigh its risks.

This review evaluates whether a risk evaluation and mitigation strategy (REMS) for the new molecular entity Imcivree (setmelanotide) is necessary to ensure the benefits outweigh its risks.

The applicant did not submit a proposed REMS or risk management plan with this application.

The Agency informed the Applicant that based on the currently available data, there were no safety issues that require a REMS for setmelanotide.

A PMR to conduct a thorough QT study to evaluate the effect of setmelanotide on the QTc interval, a PMC to develop an appropriate companion diagnostic device, and a PMC to improve the performance and repeatability of the setmelanotide confirmatory ADA assay.

A PMC to improve setmelanotide confirmatory assay reliability and reproducibility has been agreed to by the Applicant.