Imcivree

— THERAPEUTIC CATEGORIES —
  • Obesity
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Imcivree Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Setmelanotide 10mg/mL; soln for SC inj; contains benzyl alcohol.

    Pharmacological Class

    Melanocortin 4 (MC4) receptor agonist.

    How Supplied

    Multiple-dose vial (1mL)—1

    How Supplied

    Imcivree injection, clear to slightly opalescent, colorless to slightly yellow solution is supplied as:

    • Package of 1 multiple-dose vial (1-mL)

    Storage

    Storage Condition: 2° C to 8° C (36° F to 46° F)

    • Unopened Vial:  Until the expiration date

    • Opened Vial:  Up to 30 days, or until the expiration date (whichever is earlier)

    Storage Condition: 2° C to 25° C (36° F to 77° F) with excursions permitted up to 30° C (86° F)*

    • Unopened or Opened Vial:  Up to 30 days, or until the expiration date (whichever is earlier)

    * If necessary, Imcivree may be stored at room temperature (≤30° C [≤86° F]) and then returned to refrigerated conditions.

    Storage Condition: >30° C (>86° F) 

    • Unopened or Opened Vial: Discard and do not use

    Manufacturer

    Rhythm Pharmaceuticals, Inc.

    Generic Availability

    NO

    Mechanism of Action

    Setmelanotide is an MC4 receptor agonist which is 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.

    Imcivree Indications

    Indications

    Chronic weight management in patients aged ≥6yrs 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); or Bardet-Biedl syndrome (BBS).

    Limitations of Use

    Not for use in obesity due to suspected POMC, PCSK1, or LEPR deficiency with POMC, PCSK1, or LEPR variants classified as benign or likely benign. Not for use in other types of obesity not related to POMC, PCSK1 or LEPR deficiency or BBS, including obesity associated with other genetic syndromes and general (polygenic) obesity.

    Imcivree Dosage and Administration

    Adult

    Confirm diagnosis. Give by SC inj at the beginning of the day into abdomen, thigh or arm; rotate inj sites. ≥12yrs: initially 2mg once daily for 2 weeks. Target dose: 3mg once daily. If starting dose is not tolerated, reduce to 1mg once daily. If the 1mg once daily dosage is tolerated for at least 1 week, increase to 2mg once daily. If the starting dose is tolerated for 2 weeks, increase to 3mg once daily. If the 3mg once daily dosage is not tolerated, decrease to 2mg once daily. Severe renal impairment (eGFR 15–29mL/min/1.73m2): initially 0.5mg once daily for 2 weeks. Target dose: 1.5mg once daily. If the starting dose is tolerated for 2 weeks, increase to 1mg once daily. If the 1mg daily dosage is tolerated for at least 1 week, increase to 1.5mg once daily. If starting dose is not tolerated, discontinue treatment.

    Children

    <6yrs: not established. Confirm diagnosis. Give by SC inj at the beginning of the day into abdomen, thigh or arm; rotate inj sites. 6–<12yrs: initially 1mg once daily for 2 weeks. Target dose: 3mg once daily. If the starting dose is not tolerated, reduce to 0.5mg once daily. If the 0.5mg once daily dosage is tolerated for at least 1 week, increase to 1mg once daily. If the starting dose is tolerated for 2 weeks, increase to 2mg once daily. If the 2mg daily dosage is not tolerated, reduce to 1mg once daily; if the 2mg is tolerated, increase to 3mg once daily.

    Renal impairment

    Patients with End Stage Renal Disease

    • End stage renal disease (eGFR <15 mL/min/1.73m2): not recommended.

    Patients with Severe Renal Impairment 

    Adults and pediatric patients ≥12 years of age:

    • Severe renal impairment (eGFR 15–29mL/min/1.73m2): initially 0.5mg SC once daily for 2 weeks. Target dose: 1.5mg SC once daily. 

      • If the starting dose is tolerated for 2 weeks, increase to 1mg once daily. If the 1mg daily dosage is tolerated for at least 1 week, increase to 1.5mg once daily. 

      • If starting dose is not tolerated, discontinue treatment.

    Pediatric patients 6–<12 years of age: 

    • Not recommended.

    Patients with Mild or Moderate Renal Impairment

    • Mild renal impairment (eGFR 60–89 mL/min/1.73m2) or moderate renal impairment (eGFR 30–59 mL/min/1.73m2): the dosage is the same as in those with normal kidney function.

    Administration

    • Prior to initiation of setmelanotide, train patients or their caregivers on proper injection technique. Instruct patients to use a 1-mL syringe with a 28- or 29-gauge needle appropriate for subcutaneous injection.

    • Remove setmelanotide from the refrigerator approximately 15 minutes prior to administration. 

    • Alternatively, warm setmelanotide prior to administration by rolling the vial gently between the palms of the hands for 60 seconds.

    • Inspect setmelanotide visually before use. It should appear clear to slightly opalescent, colorless to slightly yellow. Do not use if particulate matter or discoloration is seen.

    • Administer setmelanotide once daily, at the beginning of the day, without regard to meals.

    • Inject setmelanotide subcutaneously in the abdomen, thigh, or arm, rotating to a different site each day. Do not administer Imcivree intravenously or intramuscularly.

    • If a dose is missed, resume the once daily regimen as prescribed with the next scheduled dose.

    Imcivree Contraindications

    Not Applicable

    Imcivree Boxed Warnings

    Not Applicable

    Imcivree Warnings/Precautions

    Warnings/Precautions

    Disturbance in sexual arousal. Monitor for new onset or worsening of depression. Suicidal ideation (consider discontinuing if occurs). Discontinue if hypersensitivity reactions occur. Monitor for skin pigmentary lesions. Perform full body skin exam prior to and during therapy. Assess weight loss after 12–16 weeks (for POMC, PCSK1, or LEPR deficiency) and after 1 year (for BBS) of therapy. Discontinue if the patient fails to lose ≥5% of baseline body weight or 5% of baseline BMI (in those with growth potential). Evaluate periodically the weight loss impact on growth and maturation in children. Severe renal impairment (aged 6–<12yrs) and ESRD (aged ≥6yrs): not recommended. Neonates/infants: risk of serious adverse reactions due to benzyl alcohol. Pregnancy: discontinue if occurs. Nursing mothers: not recommended.

    Warnings/Precautions

    Disturbance in Sexual Arousal

    • Sexual adverse reactions may occur in patients treated with setmelanotide. Spontaneous penile erections in males (24%) and sexual adverse reactions in females (7% in setmelanotide-treated patients and 0% in placebo-treated patients from an unapproved population) occurred in clinical studies with setmelanotide.

    Depression and Suicidal Ideation

    • Some drugs that target the central nervous system, such as setmelanotide, may cause depression or suicidal ideation. Depression (26%) and suicidal ideation (11%) occurred in adults and pediatric patients in setmelanotide clinical studies. Patients with a history of depression or suicidal ideation may be at increased risk for recurrent episodes while taking setmelanotide. Monitor patients for new onset or worsening of depression, suicidal thoughts or behavior, or any unusual changes in mood or behavior. Consider discontinuing setmelanotide if patients experience suicidal thoughts or behaviors or if clinically significant or persistent depression symptoms occur.

    Hypersensitivity Reactions

    • Serious hypersensitivity reactions, including anaphylaxis, have been reported, which have occurred within minutes to hours after administration of Imcivree. Discontinue use of Imcivree if hypersensitivity reactions occur and promptly seek medical attention.

    Skin Pigmentation and Darkening of Pre-Existing Nevi

    • Generalized increased skin pigmentation occurred in the majority of patients (69%) treated with setmelanotide in clinical trials. Setmelanotide may also cause darkening of pre-existing nevi due to its pharmacologic effect. This effect is reversible upon discontinuation of the drug. Perform a full body skin examination prior to initiation and periodically during treatment with setmelanotide to monitor pre-existing and new skin pigmentary lesions.

    Risk of Serious Adverse Reactions Due to Benzyl Alcohol Preservative in Neonates and Low Birth Weight Infants 

    • Setmelanotide is not approved for use in neonates or infants. Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low birth weight infants treated with benzyl alcohol-preserved drugs, including setmelanotide. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known (setmelanotide contains 10 mg of benzyl alcohol per mL).

    Pregnancy Considerations

    Discontinue setmelanotide when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus.

    Setmelanotide contains the preservative benzyl alcohol. Adverse reactions have occurred in premature neonates and low birth weight infants who received intravenously administered benzyl alcohol-containing drugs. 

    There are no available data with setmelanotide in pregnant women to inform a drug-associated risk for major birth defects and miscarriage, or adverse maternal or fetal outcomes. For the general US population, weight loss offers no potential benefit to a pregnant woman and may result in fetal harm.

    Nursing Mother Considerations

    Treatment with setmelanotide is not recommended for use while breastfeeding. 

    There is no information on the presence of setmelanotide or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. However, setmelanotide is present in the milk of animals during studies.

    Pediatric Considerations

    The safety and effectiveness of setmelanotide have not been established in pediatric patients younger than 6 years old. 

    Setmelanotide is not approved for use in neonates or infants. Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low birth weight infants treated with benzyl alcohol-preserved drugs, including setmelanotide. 

    Geriatric Considerations

    Clinical studies of setmelanotide did not include patients 65 years of age and older. It is not known whether geriatric patients would respond differently than younger adult patients.

    Renal Impairment Considerations

    Patients with severe renal impairment have a higher exposure of setmelanotide relative to patients with normal kidney function. 

    Reduce the recommended starting and target dosage of setmelanotide in adults and pediatric patients 12 years of age and older with severe renal impairment (eGFR 15–29 mL/min/1.73m2). The use of setmelanotide in pediatric patients 6–<12 years of age with severe renal impairment is not recommended.

    The recommended dosage in patients with mild (eGFR of 60–89 mL/min/1.73m2) or moderate renal impairment (eGFR of 30–59 mL/min/1.73m2) is the same as those with normal kidney function.

    Setmelanotide is not recommended for use in patients with end stage renal disease (eGFR <15 mL/min/1.73m2).

    Imcivree Pharmacokinetics

    Absorption

    After subcutaneous injection, plasma concentrations of setmelanotide reached maximum concentrations at a median tmax of 8 h after dosing.

    Distribution

    The mean apparent volume of distribution after subcutaneous administration of setmelanotide 3 mg once daily was estimated to be 48.7 L. Plasma protein bound: 79.1%.

    Metabolism

    Catabolic pathways.

    Elimination

    Half-life (t½): ~11 hours. Approximately 39% of the administered setmelanotide dose was excreted unchanged in urine during the 24-hour dosing interval after SC administration of 3 mg once daily.

    Imcivree Interactions

    Not Applicable

    Imcivree Adverse Reactions

    Adverse Reactions

    Inj site reactions, skin hyperpigmentation, nausea, headache, diarrhea, abdominal pain, back pain, fatigue, vomiting, depression, upper RTI, spontaneous penile erection.

    Imcivree Clinical Trials

    Clinical Trials

    POMC, PCSK1, and LEPR Deficiency

    The safety and efficacy of setmelanotide for chronic weight management in adult and pediatric patients 6 years of age and older with obesity due to POMC, PCSK1, or LEPR deficiency were assessed in 2 identically designed, 1-year, open-label studies, each with an 8-week, double-blind withdrawal period.

    • Study 1 (NCT02896192) enrolled patients with obesity and genetically confirmed or suspected POMC or PCSK1 deficiency.

    • Study 2 (NCT03287960) enrolled patients with obesity and genetically confirmed or suspected LEPR deficiency.

    In both studies:

    • The local genetic testing results were centrally confirmed using Sanger sequencing. 

    • Adult patients had a body mass index (BMI) of ≥30 kg/m2. 

    • Weight in pediatric patients was ≥95th percentile using growth chart assessments.

    Efficacy analyses were conducted in 21 patients (10 in Study 1; 11 in Study 2) who had completed at least 1 year of treatment at the time of a prespecified data cutoff.

    Of the 21 patients included in the efficacy analysis in Studies 1 and 2, 62% were adults and 38% were pediatric patients ≤16 years.

    • In Study 1, 50% of patients were female, 70% were White, and the median BMI was 40 kg/m2 (range: 26.6-53.3) at baseline.

    • In Study 2, 73% of patients were female, 91% were White, and the median BMI was 46.6 kg/m2 (range: 35.8-64.6) at baseline.

    The primary end point for both studies assessed the percentage of patients with at least 10% weight loss; 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”).

    In Study 1, results 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.

    In Study 2, results showed 46% (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 -3.4.

    Bardet-Biedl Syndrome

    The safety and efficacy of setmelanotide for chronic weight management in adult and pediatric patients aged 6 years and older with obesity and a clinical diagnosis of Bardet-Biedl syndrome (BBS) were assessed in a 66-week clinical study, which included a 14-week randomized, double-blind, placebo-controlled period and a 52-week open-label period (Study 3 [NCT03746522]). In the study, enrolled adult patients had a BMI of ≥30 kg/m2 and pediatric patients had weight ≥97th percentile using growth chart assessments.

    Eligible patients were entered into a 14-week, randomized, double-blind, placebo-controlled treatment period (Period 1) in which patients received setmelanotide or placebo, followed by a 52- week open-label treatment period (Period 2) in which all patients received setmelanotide. 

    Efficacy analyses were conducted in 44 patients at the end of Period 1 (Week 14, placebo-controlled data) and in 31 patients during the active-treatment period, defined as the period from randomization to Week 52 in patients initially randomized to setmelanotide, and from Week 14 to Week 66 in patients initially randomized to placebo. Analyses of the active-treatment period include patients who had either completed 52 weeks from the start of setmelanotide treatment or discontinued the study early at the time of the prespecified data cutoff.

    A total of 44 patients with obesity and a clinical diagnosis of BBS were enrolled; 50% were adults, 32% were aged 12 to <18 years, and 18% were aged 6 to <12 years; 46% were male; 77% were White, 5% were Black, 2% were Asian, and 16% had an unknown or not reported race; 2% were Hispanic or Latino and 14% had an unknown or not reported ethnicity; and the mean BMI was 41.5 kg/m2 (range: 24.4-66.1 kg/m2) at baseline.

    In Study 3, results showed the mean percent change in BMI after 52 weeks of Imcivree treatment was -7.9% (95% CI: -10.4, -5.5), 61.3% (95% CI: 42.2, 78.2) of patients achieved a ≥5% BMI decrease from baseline, and 38.7% (95% CI: 21.8, 57.8) had a ≥10% decrease in BMI.

    During the 14-week double-blind, placebo-controlled portion of Study 3 (Period 1), there was a statistically significant difference in BMI reduction between the setmelanotide-treated group and the placebo-treated group (placebo-adjusted difference: -4.5 [95% CI: -6.5, -2.5]).

    Additionally, hunger scores decreased in setmelanotide-treated patients during the 14-week placebo-controlled period and during the open-label treatment period. 

    Imcivree Note

    Not Applicable

    Imcivree Patient Counseling

    Patient Counseling

    Disturbance in Sexual Arousal

    • Sexual adverse reactions, including spontaneous erection, may occur in those treated with setmelanotide. 

    • Inform patients to seek emergency medical treatment if an erection lasts longer than 4 hours.

    Depression and Suicidal Ideation

    • Setmelanotide may cause depression or suicidal ideation. 

    • Advise patients to report any new or worsening symptoms of depression, suicidal thoughts or behaviors, or unusual changes in mood or behavior.

    Skin Pigmentation and Darkening of Pre-Existing Nevi

    • Skin darkening occurs in the majority of those treated with setmelanotide because of its mechanism of action. This change is reversable upon discontinuation of treatment.

    • Obtain a full body skin examination before starting and during treatment with setmelanotide to monitor these changes.

    Pregnancy

    • Patients who may become pregnant should inform their healthcare provider of a known or suspected pregnancy.

    Lactation

    • Treatment with setmelanotide is not recommended while breastfeeding.

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