Imcivree (setmelanotide) - 2 Indications

Scroll down for more information on each indication:

• for chronic weight management in patients with obesity due to POMC, PCSK1 or LEPR deficiency; approved December 2020
• for the treatment of Bardet-Biedl syndrome; approved June of 2022

General Information

Imcivree (setmelanotide) is a melanocortin 4 (MC4) receptor agonist, designed to restore impaired MC4 receptor pathway activity arising due to genetic deficits upstream of the MC4 receptor.

Imcivree is specifically indicated:

• for chronic weight management in adult and pediatric patients 6 years of age 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.
• for chronic weight management in adult and pediatric patients 6 years of age and older with monogenic or syndromic obesity due to BBS

Imcivree is supplied as an injection for subcutaneous administration. The recommended dosing is as follows:

Dosage in Adults and Pediatric Patients 12 Years of Age and Older

• The starting dose of Imcivree is 2 mg (0.2 mL) injected subcutaneously once daily for 2 weeks. Monitor patients for gastrointestinal (GI) adverse reactions.
• If the starting dose is not tolerated, reduce to 1 mg (0.1 mL) once daily. If the 1 mg once daily dose is tolerated and additional weight loss is desired, titrate to 2 mg (0.2 mL) once daily.
• If the 2 mg daily dose is tolerated and additional weight loss is desired, increase the dose to 3 mg (0.3 mL) once daily. If the 3 mg once daily dose is not tolerated, maintain administration of 2 mg (0.2 mL) once daily.

Dosage in Pediatric Patients 6 to less than 12 Years of Age

• For pediatric patients aged 6 to less than 12 years, the starting dose of Imcivree is 1 mg (0.1 mL) injected subcutaneously once daily for 2 weeks. Monitor patients for GI adverse reactions.
• If the starting dose is not tolerated, reduce to 0.5 mg (0.05 mL) once daily. If the 0.5 mg once daily dose is tolerated and additional weight loss is desired, the dose may be increased to 1 mg (0.1 mL) once daily.
• If the 1 mg dose is tolerated, increase the dose to 2 mg (0.2 mL) once daily.
• If the 2 mg once daily dose is not tolerated, reduce to 1 mg (0.1 mL) once daily. If the 2 mg once daily dose is tolerated and additional weight loss is desired, the dose may be increased to 3 mg (0.3 mL) once daily.

Mechanism of Action

Imcivree (setmelanotide) is a melanocortin 4 (MC4) receptor agonist, designed to restore impaired MC4 receptor pathway activity arising due to genetic deficits upstream of the MC4 receptor. MC4 receptors in the brain are involved in regulation of hunger, satiety, and energy expenditure. In patients with obesity due to POMC, PCSK1, and LEPR deficiency associated with insufficient activation of the MC4 receptor, setmelanotide may re-establish MC4 receptor pathway activity to reduce hunger and promote weight loss through decreased caloric intake and increased energy expenditure. Nonclinical evidence shows that MC4 receptors are important for setmelanotide-regulated appetite and weight loss. The MC1 receptor is expressed on melanocytes, and activation of this receptor leads to accumulation of melanin and increased skin pigmentation independently of ultraviolet light.

Side Effects

Adverse effects associated with the use of Imcivree may include, but are not limited to, the following:

• injection site reactions
• skin hyperpigmentation
• nausea
• headache
• diarrhea
• abdominal pain
• back pain
• fatigue
• vomiting
• depression
• upper respiratory tract infection
• spontaneous penile erection

Indication 1 - chronic weight management in patients with obesity due to POMC, PCSK1 or LEPR deficiency

Clinical Trial Results

The FDA approval of  Imcivree was based on two identically designed, 1-year, open-label studies, each with an 8-week, double-blind withdrawal period. Study 1 enrolled patients aged 6 years and above with obesity and genetically confirmed or suspected POMC or PCSK1 deficiency, and Study 2 enrolled patients aged 6 years and above with obesity and genetically confirmed or suspected LEPR deficiency. In both studies, adult patients had a body mass index (BMI) of ≥30 kg/m2 . Weight in pediatric patients was ≥95th percentile using growth chart assessments. Dose titration occurred over a 2- to 12-week period, followed by a 10-week, open-label treatment period. Patients who achieved at least a 5-kilogram weight loss (or at least 5% weight loss if baseline body weight was <100 kg) at the end of the open-label treatment period continued into a double-blind withdrawal period lasting 8 weeks, including 4 weeks of Imcivree followed by 4 weeks of placebo (investigators and patients were blinded to this sequence). Following the withdrawal sequence, patients re-initiated active treatment with Imcivree at the therapeutic dose for up to 32 weeks.

Efficacy analyses were conducted in 21 patients (10 in Study 1 and 11 in Study 2) who had completed at least 1 year of treatment at the time of a prespecified data cutoff. Six additional patients enrolled in the studies (4 in Study 1 and 2 in Study 2) who had not yet completed 1 year of treatment at the time of the cutoff were not included the efficacy analyses.

In Study 1, 80% of patients with obesity due to POMC or PCSK1 deficiency met the primary endpoint, achieving a ≥10% weight loss after 1 year of treatment with Imcivree. In Study 2, 46% of patients with obesity due to LEPR deficiency achieved a ≥10% weight loss after 1 year of treatment with Imcivree . When treatment was withdrawn in the 16 patients who had lost at least 5 kg (or 5% of body weight if baseline body weight was <100 kg) during the 10-week open-label period, these patients gained an average of 5.5 kg in Study 1 and 5.0 kg in Study 2 over 4 weeks. Re-initiation of treatment with Imcivree resulted in subsequent weight loss.

Indication 2 - chronic weight management in adult and pediatric patients 6 years of age and older with monogenic or syndromic obesity due to BBS

Clinical Trial Results

The FDA approval for BBS was based on data from a pivotal Phase 3 clinical trial in 31 patients aged ≥6 years with obesity due to BBS. In the clinical trial, Imcivree delivered early, significant and sustained weight reduction. The trial met its primary endpoint and all key secondary endpoints, with statistically significant reductions in weight and hunger at 52 weeks on therapy. The mean percent change in BMI was -7.9% without requirements for diet and exercise. The placebo-adjusted change in BMI was -4.5% in a 14-week double-blind placebo-controlled stage (Imcivree n=22; -4.6% change in BMI; placebo n=22; -0.1% change in BMI) and there was statistically significant mean change in hunger score of -2.1 at 52 weeks in patients 12 years and older who were able to self-report their hunger (n=14).