Peptide Profile
Setmelanotide
Targeted MC4R agonist for rare genetic obesity caused by melanocortin pathway defects
Dose Range
0.5 mg-3 mgmg
Frequency
Once daily
Route
subcutaneous injection
Cycle Length
Ongoing/indefinite
Onset
Moderate (1-2 weeks)
Evidence
Strong
Compound Profile
Scientific & Efficacy Data
C49H68N18O9S2
Molecular Formula
1,117.3 Da
Molecular Weight
~11 hours
Half-Life
~79% subcutaneous bioavailability
Bioavailability
920014-72-8
CAS #
11993702
PubChem ID ↗
Developed By · 2020
Rhythm Pharmaceuticals
Rhythm Pharmaceuticals
Primary Benefits
Dramatic weight reduction (10-23%) in patients with rare genetic obesity by restoring MC4R-mediated satiety signaling that is absent due to upstream pathway mutations
Comprehensive metabolic improvement including BMI reduction, improved lipid profiles, and resolution of hyperphagia-driven metabolic dysfunction
Transformative reduction in insatiable hunger (hyperphagia) that characterizes monogenic obesity, dramatically improving daily functioning and psychosocial wellbeing
Amino Acid Sequence
H-Nle4-D-Phe7-Arg8-Trp9-Lys10(Ac-γ-MSH-analogue)-NH2Dosing
How much
do I take?
Timing
Best time to take
Administer Setmelanotide at the same time each day (or on the same day each week for weekly injections). Many users prefer morning or evening administration. Pick a time you'll remember consistently.
With food?
Setmelanotide injections can be given regardless of meal timing. However, if GI effects occur, administering on an empty stomach or with a light meal may help reduce discomfort.
If stacking
Setmelanotide should be used as directed by your healthcare provider. If combining with other medications or supplements, discuss potential interactions with your provider. Avoid combining with compounds that have overlapping mechanisms unless specifically guided by a medical professional.
Adjusting Your Dose
Increase if
- +You've tolerated the current dose for the recommended period without significant side effects
- +Therapeutic goals haven't been met at the current dose level
- +Your healthcare provider recommends dose escalation based on your response
- +Lab work or clinical assessments support a higher dose
Decrease if
- -Side effects are bothersome or impacting daily life despite management strategies
- -You experience any signs of an adverse reaction
- -Lab results indicate the need for dose reduction
- -Your healthcare provider recommends a lower dose based on your response
Signs of right dose
- ✓Therapeutic goals being met with minimal side effects
- ✓Stable and consistent response to treatment
- ✓Lab values or clinical markers trending in the right direction
- ✓Good tolerance with manageable or absent side effects
Dosing Calculator
Calculate Your Exact Dose
Step 1: Peptide Weight
Find the weight printed on your peptide vial label
Look here!
The peptide weight is printed on the label
Look here!
The weight is on the label
Suitability
Is this
right for me?
Best For
Treating obesity caused by confirmed POMC deficiency mutations
Setmelanotide is particularly well-suited for individuals focused on treating obesity caused by confirmed pomc deficiency mutations. Research and clinical experience suggest meaningful benefits in this area when used as part of a comprehensive treatment approach.
Managing obesity from PCSK1 or LEPR genetic defects
Setmelanotide is particularly well-suited for individuals focused on managing obesity from pcsk1 or lepr genetic defects. Research and clinical experience suggest meaningful benefits in this area when used as part of a comprehensive treatment approach.
Reducing hyperphagia and body weight in Bardet-Biedl syndrome
Setmelanotide is particularly well-suited for individuals focused on reducing hyperphagia and body weight in bardet-biedl syndrome. Research and clinical experience suggest meaningful benefits in this area when used as part of a comprehensive treatment approach.
Addressing early-onset severe obesity with identified melanocortin pathway mutations
Setmelanotide is particularly well-suited for individuals focused on addressing early-onset severe obesity with identified melanocortin pathway mutations. Research and clinical experience suggest meaningful benefits in this area when used as part of a comprehensive treatment approach.
Consider Alternatives If
Who Should Avoid
Do not use if
- ×Known hypersensitivity to setmelanotide or any excipients
- ×Obesity not caused by POMC, PCSK1, LEPR deficiency or Bardet-Biedl syndrome
- ×Patients without genetic confirmation of melanocortin pathway mutations
- ×Use during pregnancy (animal studies suggest potential fetal harm)
Use with caution if
- !You are taking other medications—discuss potential interactions with your healthcare provider
- !You have a history of liver or kidney disease
- !You are elderly or have multiple medical conditions
- !You are planning surgery in the near future—inform your surgeon about Setmelanotide use
- !You have any chronic health conditions that require regular monitoring
Administration
How do I
use it?
Reconstitution
What you need
- •Setmelanotide vial (lyophilized powder or solution)
- •Bacteriostatic water or sterile sodium chloride for reconstitution
- •Alcohol swabs for cleaning vial tops and injection sites
- •Appropriately sized syringes with fine-gauge needles (27-30 gauge)
- •Sharps disposal container
Injection
Route
Subcutaneous injection (into the fatty tissue just under the skin)—allows for consistent absorption and can be self-administered at home after proper training
Best sites
- •Abdomen (stomach area)—at least 2 inches from the belly button, most popular choice for self-injection
- •Front of thighs—middle to upper portion of the outer leg
- •Back of upper arm—outer area (may need assistance from another person)
Technique
- 1.Wash your hands thoroughly with soap and water before handling supplies
- 2.Clean the injection site with an alcohol swab and let it air dry completely
- 3.Pinch a fold of skin at the chosen injection site
- 4.Insert the needle at a 45-90 degree angle (depending on needle length and body composition)
- 5.Inject the medication slowly and steadily over 5-10 seconds
- 6.Release the skin fold and remove the needle, applying gentle pressure with a clean swab
- 7.Rotate injection sites to prevent tissue irritation or lipodystrophy
- 8.Dispose of the needle safely in a sharps container—never recap or reuse needles
Storage
Signs of degradation
Sample Daily Schedule
Safety
Is it
safe?
Safety Profile
Setmelanotide demonstrates favorable tolerability in Phase 3 trials with safety data from over 200 patients across POMC, PCSK1, LEPR-deficient, and Bardet-Biedl syndrome populations. The most common adverse effect is dose-dependent skin hyperpigmentation (>60% of patients) due to off-target MC1R activation on melanocytes—a manageable, reversible pharmacological effect rather than true toxicity. Serious psychiatric adverse events including depression and suicidal ideation require baseline mental health screening and ongoing monitoring in all patients.
Safety evidence comes from Phase 3 trials (IMCIVREE, VENTURE) in pediatric and adult populations with confirmed genetic melanocortin pathway defects, with long-term follow-up data supporting chronic administration. FDA approval in 2020 and EMA approval in 2021 validate the benefit-risk profile in eligible populations. Ongoing Phase 2 studies in hypothalamic obesity, Prader-Willi syndrome, and Alström syndrome continue to characterize safety in expanded indications.
Common Side Effects
Experienced by some users
Skin Hyperpigmentation
The most characteristic side effect, occurring in >60% of patients. Results from off-target activation of MC1R on melanocytes. Manifests as generalized darkening of skin that develops gradually over weeks to months.
Management: Expected pharmacological effect of melanocortin receptor activation. Monitor skin changes at regular intervals. Perform baseline and periodic skin examinations including dermoscopy for nevus surveillance. Hyperpigmentation may partially reverse upon treatment discontinuation.
Injection Site Reactions
Local reactions including erythema, pruritus, induration, and mild pain at the injection site. Reported in approximately 20-30% of patients in clinical trials.
Management: Rotate injection sites between abdomen, thigh, and upper arm. Clean site before injection. Apply cold compress if needed. Reactions typically mild and self-limiting.
Nausea
Reported in clinical trials, typically mild to moderate. May be related to central MC4R-mediated effects on appetite and gastrointestinal motility.
Management: Usually resolves with continued treatment. Take with food if helpful. Slow dose titration may reduce incidence.
Diarrhea
Gastrointestinal disturbance reported in some patients, generally mild and transient.
Management: Maintain adequate hydration. Typically self-limiting and does not require dose adjustment.
Less Common
- •Hair Color Darkening and Nevus Changes
These typically resolve with continued use or dose adjustment.
Stop and Seek Help If
- ×Severe or worsening side effects that don't improve with dose adjustment or supportive care
- ×Signs of an allergic reaction—rash, hives, swelling, or difficulty breathing
- ×Your healthcare provider recommends discontinuation based on your clinical response
- ×Development of any new medical condition that may be contraindicated with Setmelanotide
- ×Pregnancy or planning to become pregnant (unless specifically approved for use during pregnancy)
- ×Abnormal lab results or clinical markers that suggest adverse effects
Setmelanotide should only be started, adjusted, or discontinued under medical supervision. This information is for educational purposes only and does not replace professional medical advice. Never stop a prescribed treatment without consulting your healthcare provider first, as abrupt discontinuation may have consequences.
Interactions
With other peptides
- ✓Essential for confirming melanocortin pathway mutations and identifying eligible patients for targeted MC4R agonist therapy
- ✓Complementary approach to support dietary and lifestyle modifications alongside pharmacological hunger reduction
- ✓Supports healthy eating patterns as hyperphagia resolves and appetite normalizes with treatment
With medications
- !Other MC4R Agonists - Redundant mechanism of action with increased risk of melanocortin-related side effects including excessive hyperpigmentation
- !Medications Affecting Melanocortin Signaling - Potential unpredictable interactions with melanocortin pathway signaling and altered efficacy or safety profile
- !Photosensitizing Agents - May exacerbate skin pigmentation changes and increase risk of melanocytic nevus development in the setting of MC1R activation
With supplements
- ✓Multivitamins - Generally safe to take alongside Setmelanotide. Space doses apart if taking oral formulations to ensure optimal absorption.
- ✓Electrolyte supplements - Helpful if experiencing any GI side effects that could lead to dehydration. Safe to combine.
Effectiveness
Does it
work?
Evidence Level
Strong human trials
What to Expect
Weeks 1-4
What you might notice
- •Beginning of dose titration from 0
- •5-1 mg
- •Possible early reduction in hunger intensity
- •Mild injection site reactions
- •Early signs of skin darkening may begin
What's normal
- •Appetite changes may be subtle initially during low-dose titration
- •Skin hyperpigmentation develops gradually
- •Mild nausea or GI changes are common and usually transient
What's next
- →Continue dose titration by 0
- →5 mg every 2 weeks
- →Monitor body weight, hunger scores, and skin changes
- →Target maintenance dose of 2-3 mg
Weeks 4-12
What you might notice
- •Meaningful reduction in hyperphagia as dose approaches maintenance level
- •Measurable weight loss beginning
- •Skin hyperpigmentation becoming more apparent
What's normal
- •Hunger reduction is typically the earliest noticeable clinical effect
- •Weight loss follows as caloric intake decreases
- •Skin darkening continues to develop and is an expected pharmacological effect
What's next
- →Achieve maintenance dose (2-3 mg)
- →Assess clinical response with weight measurements and hyperphagia questionnaires
- →Begin regular dermatological monitoring
Weeks 12-52
What you might notice
- •Sustained weight loss with many patients achieving >10% body weight reduction
- •Significant and sustained hyperphagia reduction
- •Stable skin pigmentation
What's normal
- •Weight loss trajectory may vary between genetic subtypes (POMC/PCSK1 patients tend to respond more robustly than LEPR or BBS)
- •Hunger suppression is typically well-maintained
- •Skin changes stabilize
What's next
- →Continue chronic maintenance therapy
- →Reassess every 3-6 months
- →If <5% weight loss after adequate trial at maximum dose, consider whether to continue
- →Long-term treatment required as weight regain occurs upon discontinuation
Signs It's Working
Treatment Response
- ✓Improvement in the primary symptoms or condition being treated
- ✓Positive changes in relevant lab values or clinical markers
- ✓Consistent, stable response to Setmelanotide over time
- ✓Reduction in symptom frequency or severity
General Well-being
- ✓Improved energy levels and daily functioning
- ✓Better quality of life related to the treated condition
- ✓Manageable or absent side effects indicating good tolerance
- ✓Positive feedback from healthcare provider during check-ups
Not Seeing Results?
Common reasons
- •Not at therapeutic dose yet—initial doses are for building tolerance, not maximum effect
- •Insufficient time at target dose—most compounds need several weeks to show full benefits
- •Inconsistent dosing schedule—regular, consistent use is crucial for optimal results
- •Individual variation in response—genetics, metabolism, and other factors affect outcomes
- •Underlying conditions or medications interfering with absorption or effectiveness
- •Improper storage leading to degraded product—always verify proper storage conditions
Key Research
"Setmelanotide: First Approval"
Markham A, 2021
Finding: Setmelanotide is the first FDA-approved medicine for a rare form of genetic obesity caused by defects in the brain's appetite control center—it activates the melanocortin-4 receptor to restore normal hunger signals in people with POMC, PCSK1, or leptin receptor deficiency.
View Study"Setmelanotide in patients aged 2-5 years with rare MC4R pathway-associated obesity (VENTURE)"
Argente J, Verge CF, Okorie U, et al., 2025
Finding: In a study of very young children (ages 2-5) with genetic obesity, setmelanotide reduced BMI by an average of 18 percent and cut hunger by 91 percent in caregivers' reports—making it the first treatment option for this age group with rare genetic forms of severe early-onset obesity.
View Study"Setmelanotide: A Melanocortin-4 Receptor Agonist for Severe Obesity Due to Hypothalamic Dysfunction"
Qamar S, Mallik R, Makaronidis J, et al., 2024
Finding: Setmelanotide represents a breakthrough in treating monogenic obesity by directly activating the brain's appetite-control receptor, offering hope for people with severe genetic obesity from POMC, PCSK1, and other leptin-melanocortin pathway defects that cause extreme hunger and early-onset weight gain.
View Study"The effect of MC4R agonist drugs on obesity and metabolic risk factors: a systematic review and meta-analysis"
Sun Y, Abed M, Sohouli MH, et al., 2025
Finding: Clinical evidence supports setmelanotide's effectiveness in managing rare genetic forms of severe obesity and hyperphagia.
View Study"Setmelanotide-mediated MC4R activation improves hypothalamic obesity via CaMKK2/AMPK pathways"
Peng J, Ou Y, Zhou M, et al., 2025
Finding: Setmelanotide demonstrates sustained efficacy in long-term weight management for patients with genetic obesity disorders.
View StudyFrequently Asked Questions