The Food and Drug Administration (FDA) has approved Imcivree™ (setmelanotide; Rhythm Pharmaceuticals) for chronic weight management in patients aged 6 years and older with obesity due to proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency confirmed by genetic testing demonstrating variants in POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance (VUS).
Imcivree is a melanocortin-4 receptor (MC4R) agonist that activates the MC4R in the brain to regulate energy expenditure and appetite. The MC4R pathway consists of variants in genes associated with early-onset obesity, including POMC and LEPR genes.
The approval was based on data from 2 pivotal multicenter, open-label, single-arm phase 3 studies that assessed the efficacy and safety of setmelanotide in patients aged 6 years and older with either POMC, PCSK1, or LEPR deficiency obesity for approximately 1 year. The study design included 12 weeks of therapeutic dose, followed by an 8-week blinded, drug withdrawal phase and lastly, 32 weeks of therapeutic dose to complete 1 year of treatment. The primary end point for both studies assessed the percentage of patients with at least 10% weight loss; key secondary end points included the mean percent reduction from baseline of body weight and hunger score responder analysis on an 11-point scale from 0 (“not hungry at all”) to 10 (“hungriest possible”).
Results from the POMC or PCSK1 deficiency study showed 80% (n=8/10) of patients met the primary end point achieving at least 10% weight loss from baseline to 1 year (95% CI: 44.4, 97.5; P <.0001); the mean reduction from baseline in body weight was -23.12% (95% CI: -31.9, -14.4; P =.0003), and the median reduction in hunger score was -2.0.
Results from the LEPR deficiency study showed 45.5% (n=5/11) of patients met the primary end point achieving at least 10% weight loss from baseline to 1 year (95% CI: 16.8, 76.6; P =.0002); the mean reduction from baseline in body weight was -9.65% (95% CI: -16.0, -3.3; P =.0074), and the median reduction in hunger score was -3.0.
As for safety, the most common adverse reactions (incidence of greater than or equal to 23%) for Imcivree were injection site reactions, skin hyperpigmentation, nausea, headache, diarrhea, abdominal pain, back pain, fatigue, vomiting, depression, upper respiratory tract infection, and spontaneous penile erection.
Imcivree is not recommended for use in patients with moderate/severe renal impairment and end stage renal disease. Patients should be advised that Imcivree may also cause spontaneous penile erections in males and sexual adverse reactions in females. Additionally, patients should be monitored for new onset or worsening of depression while taking Imcivree.
“This FDA approval marks an important turning point, providing a much needed therapy and supporting the use of genetic testing to identify and properly diagnose patients with these rare genetic diseases of obesity,” said Jennifer Miller, MD, pediatric endocrinologist at University of Florida Health.
The FDA previously granted Breakthrough Therapy, Orphan Drug designations and Priority Review to Imcivree for this application. The Company is also investigating setmelanotide in patients with Bardet-Biedl or Alström syndrome.
Imcivree will be supplied as 10mg/mL of setmelanotide in 1mL multiple-dose vials and is expected to be available in the first quarter of 2021.
For more information visit imcivree.com.
1. FDA approves first treatment for weight management for people with certain rare genetic conditions. [press release]. Silver Springs, MD: US Food and Drug Administration; November 27, 2020.
2. Rhythm Pharmaceuticals announces FDA approval of Imcivree™ (setmelanotide) as first-ever therapy for chronic weight management in patients with obesity due to POMC, PCSK1 or LEPR deficiency. [press release]. Boston, MA: Rhythm Pharmaceuticals; November 27, 2020.
3. Imcivree™ [package insert]. Boston, MA: Rhythm Pharmaceuticals; 2020.