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

In patients with obesity due to POMC, PCSK1, or LEPR deficiency the first and only treatment to target a root cause of obesity

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
POMC, PCSK1, and LEPR deficiency are biallelic genetic diseases that include homozygous and compound heterozygous genotypes5

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

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.


BASELINE CHARACTERISTICS IN THE IMCIVREE TRIALS4,5

Baseline Characteristics Baseline Characteristics

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

Efficacy

In patients with obesity due to POMC, PCSK1, or LEPR deficiency IMCIVREE delivered significant, clinically meaningful weight loss over 1 year4

Mean % change in body weight over 1 year

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

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

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


In patients with obesity due to POMC, PCSK1, or LEPR deficiency IMCIVREE decreased hunger over 1 year4

Median change in maximal hunger score over 1 year

POMC or PCSK1 (n=8)*
  • 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 (n=8)*†
  • 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

LEPR, leptin receptor; PCSK1, proprotein convertase subtilisin/kexin type 1; POMC, pro-opiomelanocortin.
*Changes 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). The median score at baseline (and week 52) was determined by calculating the average week 1 score (and average week 52 score) for each patient and determining for the median for the group.
Three 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 of 1-year duration4

  • IMCIVREE is an MC4 receptor agonist with some activity at the melanocortin 1 (MC1) receptors; activation of MC1 leads to accumulation of melanin and increased skin pigmentation. This effect is reversible upon discontinuation of treatment4
  • Perform a full body skin examination prior to initiation and periodically during treatment to monitor pre-existing and new skin pigmentary lesions4
  • Changes in skin pigmentation or hair color primarily occurred within the first month of treatment7
  • Injection site reactions, nausea, and vomiting most often occurred within the first month after starting treatment, and then decreased over time7

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 Dec;8(12):960-970. doi: 10.1016/S2213-8587(20)30364-8. Epub 2020 Oct 30. PMID: 33137293. 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. 7. Data on file. Rhythm Pharmaceuticals, Inc. Boston, MA.

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.