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