Mechanism of Action

THE MELANOCORTIN-4 RECEPTOR (MC4R) SIGNALING PATHWAY REGULATES APPETITE AND ENERGY EXPENDITURE1-3

Interrupted MC4R Pathway Interrupted MC4R Pathway

Genetic variants in this pathway can lead to insatiable
hunger and severe obesity

IMCIVREE is the first and only treatment to target a root cause of obesity in patients with obesity due to POMC, PCSK1, OR LEPR deficiency

IMCIVREE may restore function in the signaling cascade responsible for regulating hunger, caloric intake, energy expenditure, and, consequently, body weight1-4

Fixed MC4R Pathway Fixed MC4R Pathway

IMCIVREE is designed to re-establish MC4R pathway function4

LEPR=leptin receptor; POMC=pro-opiomelanocortin; PCSK1=proprotein convertase subtilisin/kexin type 1; MSH=melanocyte-stimulating hormone.

TRIAL OVERVIEW

IMCIVREE WAS STUDIED IN 2 IDENTICALLY DESIGNED, 1-YEAR, OPEN-LABEL STUDIES, EACH WITH AN 8-WEEK, DOUBLE-BLIND WITHDRAWAL PERIOD4,5

Trial Overview Trial Overview
Primary endpoint:
  • Proportion of participants who achieve ≥10% weight loss at 1 year of treatment (POMC or PCSK1, N=10; LEPR, N=11)

aOnly participants who lost ≥5 kg weight (or ≥5% of body weight if baseline weight was <100 kg) in the first open-label active treatment phase entered an 8-week, double-blind withdrawal period, including 4 weeks of IMCIVREE followed by 4 weeks of placebo.


BASELINE CHARACTERISTICS IN THE IMCIVREE TRIALS4

Baseline Characteristics Baseline Characteristics

POMC=pro-opiomelanocortin; PCSK1=proprotein convertase subtilisin/kexin type 1; LEPR=leptin receptor; SD=standard deviation; BMI=body mass index.

Efficacy

IMCIVREE delivered significant, clinically meaningful weight loss over 1 year4

Weight loss over time

POMC or PCSK1 deficiency (n=9)a
  • 80% of patients with obesity due to POMC or PCSK1 deficiency achieved a ≥10% weight loss from baseline after 1 year
    (95% CI: 44.4%, 97.5%); P<0.0001; N=10
  • IMCIVREE demonstrated a 23.1% mean reduction in weight from baseline after 1 year
    (95% CI: -31.9%, -14.4%); P=0.0003; N=10
LEPR deficiency (n=7)a
  • 45.5% of patients with obesity due to LEPR deficiency achieved a ≥10% weight loss from baseline after 1 year
    (90% CI: 16.8%, 76.6%); P=0.0002; N=11
  • IMCIVREE demonstrated a 9.7% mean reduction in weight from baseline after 1 year
    (95% CI: -16.0%, -3.3%); P=0.0074; N=11

In both studies, weight increased during the withdrawal period, then decreased once treatment was reinitiated4

POMC=pro-opiomelanocortin; PCSK1=proprotein convertase subtilisin/kexin type 1; LEPR=leptin receptor; BL=baseline; FV=final visit; CI=confidence interval.
aParticipants who achieved weight loss threshold (≥5 kg or 5% if baseline body weight was <100 kg) during the 10-week open-label period.
bThe withdrawal period lasted 8 weeks, which included 4 weeks of IMCIVREE followed by 4 weeks of placebo.


IMCIVREE decreased hunger over 1 year4

Median change in maximal hunger score over 1 year

POMC or PCSK1 deficiency (n=8)a
  • In patients with obesity due to POMC or PCSK1 deficiency, IMCIVREE demonstrated a median 2-point reduction in maximal hunger score at 1 year
    (Range: -6.5, -0.1)
LEPR deficiency (n=8)ab
  • In patients with obesity due to LEPR deficiency, IMCIVREE demonstrated a median 3.4-point reduction in maximal hunger score at 1 year
    (Range: -4.7, 1.0)

When treatment was withdrawn, hunger scores generally worsened and then improved when IMCIVREE was reinitiated4

POMC=pro-opiomelanocortin; PCSK1=proprotein convertase subtilisin/kexin type 1; LEPR=leptin receptor.
aChanges in patient-reported maximal hunger over the previous 24 hours were assessed by the Daily Hunger Questionnaire Item 2 for subjects aged ≥12 years, with a hunger score ranging from 0 (not hungry at all) to 10 (hungriest possible).
bThree patients had missing hunger data at 1 year.

Safety

Adverse reactions

Adverse reactions occurring in ≥23% of patients treated with IMCIVREE in open-label clinical studies over 1 year4

  • IMCIVREE may cause generalized increased skin pigmentation and 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 to monitor pre-existing and new skin pigmentary lesions

An extension study evaluating long-term outcomes for
patients on IMCIVREE is ongoing6

aIncludes injection site erythema, pruritus, edema, pain, induration, bruising, hypersensitivity, hematoma, nodule, and discoloration.
bIncludes skin hyperpigmentation, pigmentation disorders, and skin discoloration.
cIncludes abdominal pain and upper abdominal pain.
dIncludes depressed mood.
en=13 male patients.

References: 1. Yazdi FT et al. PeerJ. 2015;3:e856. 2. Shen W-J et al. Biochim Biophys Acta Mol Basis Dis. 2017;1863:2477-2485. 3. Farooqi IS, O’Rahilly S. J Endocrinol. 2014;223:T63-T70. 4. IMCIVREE [prescribing information]. Boston, MA. Rhythm Pharmaceuticals, Inc. 5. Clément K et al. Lancet Diabetes Endocrinol. 2020;8(12):960-970. Supplemental appendix available at: doi.org/10.1016/S2213-8587(20)3036. 6. Long term extension trial of setmelanotide. ClinicalTrials.gov identifier: NCT03651765. Updated December 31, 2020. Accessed January 5, 2021. https://clinicaltrials.gov/ct2/show/NCT03651765.

Important Safety Information
WARNINGS AND PRECAUTIONS

Disturbance in Sexual Arousal: Sexual adverse reactions may occur in patients treated with IMCIVREE. Spontaneous penile erections in males and sexual adverse reactions in females occurred in clinical studies with IMCIVREE.

Depression and Suicidal Ideation: Some drugs that target the central nervous system, such as IMCIVREE, may cause depression or suicidal ideation. Monitor patients for new onset or worsening of depression. Consider discontinuing IMCIVREE if patients experience suicidal thoughts or behaviors.

Indication

IMCIVREE is indicated for chronic weight management in adult and pediatric patients 6 years of age and older with proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency obesity.