Setmelanotide (Imcivree®): A Comprehensive Pharmacological and Clinical Monograph

1.0 Executive Summary of Setmelanotide (Imcivree®)

Setmelanotide, marketed under the brand name Imcivree®, represents a first-in-class precision medicine for the chronic management of weight in individuals with specific rare genetic disorders of obesity.[1] It is a potent, selective agonist of the melanocortin 4 receptor (MC4R), a critical component of the hypothalamic signaling pathway that governs hunger, satiety, and energy expenditure.[4] The therapeutic rationale for Setmelanotide is to restore function to this pathway when it is impaired by upstream genetic defects.

The medication is specifically indicated for chronic weight management in adults and children (aged 2 years and older) with obesity due to deficiencies in pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or the leptin receptor (LEPR), as confirmed by an FDA-approved genetic test.[2] Its indication has also been expanded to include Bardet-Biedl syndrome (BBS), another rare genetic disorder where MC4R pathway function is compromised.[5] Setmelanotide is not effective for and is not indicated in the treatment of general (polygenic) obesity or in cases where genetic variants are classified as benign.[1]

Pivotal clinical trials have demonstrated significant efficacy, with 80% of patients with POMC/PCSK1 deficiency and 45.5% of patients with LEPR deficiency achieving at least a 10% reduction in body weight after one year of treatment.[3] Efficacy has also been established in BBS, with a significant proportion of patients achieving meaningful weight loss and reduction in hunger scores.[12]

The safety profile of Setmelanotide is well-characterized. The most common adverse events include injection site reactions, skin hyperpigmentation, nausea, and headache.[1] Important warnings and precautions include the potential for disturbances in sexual arousal (e.g., spontaneous penile erections), depression and suicidal ideation, and mechanism-related skin hyperpigmentation due to off-target activity at the melanocortin 1 receptor (MC1R).[1] The formulation contains benzyl alcohol, precluding its use in neonates and low-birth-weight infants due to the risk of toxicity.[2] Administered as a once-daily subcutaneous injection, Setmelanotide's favorable pharmacokinetic profile supports patient adherence and long-term management.[5]

2.0 Drug Identification and Physicochemical Properties

2.1 Nomenclature and Identifiers

Setmelanotide is identified by a comprehensive set of names, developmental codes, and registry numbers that ensure its unambiguous characterization in scientific, clinical, and regulatory contexts.

• Generic Name: The universally recognized generic name is Setmelanotide.[4] International Nonproprietary Name (INN) variants include Setmelanotida, Setmélanotide, and Setmelanotidum.[4]
• Brand Name: The drug is marketed exclusively under the brand name Imcivree®.[1]
• Synonyms and Developmental Codes: During its development, Setmelanotide was known by several codes, which are essential for tracing its research history. These include RM-493, BIM-22493, and IRC-022493.[16]
• Standard Identifiers: The compound is cataloged in major chemical and drug databases under specific identifiers. Its DrugBank Accession Number is DB11700.[4] The Chemical Abstracts Service (CAS) Registry Number for the free base form of the molecule is 920014-72-8.[5] Related CAS numbers for its salt forms include 1504602-49-6 for Setmelanotide acetate and 1301120-74-0 for Setmelanotide pamoate.[19]

2.2 Chemical Structure and Classification

Setmelanotide is a synthetic, small-molecule therapeutic agent classified as a cyclic oligopeptide.[4] Its structure is meticulously designed to optimize potency, selectivity, and pharmacokinetic properties.

• Compound Class: As an oligopeptide, it is composed of a short chain of amino acids linked by peptide bonds. Specifically, it is an eight-amino-acid cyclic peptide.[5]
• Peptide Sequence: The primary structure of Setmelanotide is defined by the following amino acid sequence: N-acetyl-L-arginyl-L-cysteinyl-D-alanyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophyl-L-cysteinamide.[16] This is often abbreviated as Ac-Arg-Cys(1)-D-Ala-His-D-Phe-Arg-Trp-Cys(1)-NH2.[1] A key structural feature is the intramolecular disulfide bond between the thiol groups of the two cysteine residues (at positions 2 and 8), which forms a cyclic structure essential for its conformation and activity.[17] The inclusion of two non-natural D-amino acids (D-Alanine and D-Phenylalanine) is a common strategy in peptide drug design to increase metabolic stability by conferring resistance to cleavage by endogenous proteases.
• Chemical Formula and Molecular Weight: The chemical formula for the anhydrous, free-base form of Setmelanotide is C49​H68​N18​O9​S2​.[4] This corresponds to a monoisotopic mass of 1116.48580819 Da and an average molecular weight of approximately 1117.3 g/mol.[4]
• IUPAC Name and Chemical Identifiers: For unambiguous chemical reference, the International Union of Pure and Applied Chemistry (IUPAC) name is (4R,7S,10S,13R,16S,19R,22R)-22-amino]-13-benzyl-10-[3-(diaminomethylideneamino)propyl]-16-(1H-imidazol-5-ylmethyl)-7-(1H-indol-3-ylmethyl)-19-methyl-6,9,12,15,18,21-hexaoxo-1,2-dithia-5,8,11,14,17,20-hexazacyclotricosane-4-carboxamide.[16] Its structure is also uniquely defined by identifiers such as the InChIKey: HDHDTKMUACZDAA-PHNIDTBTSA-N.[16]

Table 2.1: Setmelanotide Identification and Chemical Properties

Identifier Type	Value
Generic Name	Setmelanotide
Brand Name	Imcivree®
DrugBank ID	DB11700
CAS Number (free base)	920014-72-8
Developmental Codes	RM-493, BIM-22493, IRC-022493
Compound Class	Cyclic Oligopeptide (Small Molecule)
Molecular Formula	C49​H68​N18​O9​S2​
Molecular Weight (Average)	1117.3 g/mol
Monoisotopic Mass	1116.48580819 Da
Peptide Sequence	Ac-Arg-Cys(1)-D-Ala-His-D-Phe-Arg-Trp-Cys(1)-NH2
IUPAC Name	(4R,7S,10S,13R,16S,19R,22R)-22-amino]-13-benzyl-10-[3-(diaminomethylideneamino)propyl]-16-(1H-imidazol-5-ylmethyl)-7-(1H-indol-3-ylmethyl)-19-methyl-6,9,12,15,18,21-hexaoxo-1,2-dithia-5,8,11,14,17,20-hexazacyclotricosane-4-carboxamide
InChIKey	HDHDTKMUACZDAA-PHNIDTBTSA-N

3.0 Preclinical and Clinical Pharmacology

3.1 Mechanism of Action: Restoring a Disrupted Pathway

The therapeutic effect of Setmelanotide is rooted in its precise intervention within a key neuroendocrine pathway responsible for regulating body weight. Its mechanism of action exemplifies a precision medicine approach, targeting the specific molecular deficit underlying certain rare genetic forms of obesity.

The hypothalamic leptin-melanocortin pathway, which converges on the melanocortin 4 receptor (MC4R), is a fundamental biological system for maintaining energy homeostasis.[5] Under normal physiological conditions, the hormone leptin, secreted by adipose tissue, binds to the leptin receptor (LEPR) on pro-opiomelanocortin (POMC)-expressing neurons in the hypothalamus. This binding event triggers a signaling cascade that includes the synthesis of the POMC precursor protein. POMC is then processed by the enzyme proprotein convertase subtilisin/kexin type 1 (PCSK1) to yield several active peptides, including alpha-melanocyte-stimulating hormone (α-MSH). Subsequently, α-MSH is released and binds to the MC4R on second-order neurons, generating a signal that promotes satiety, reduces hunger, and increases energy expenditure.[11]

In the rare genetic disorders for which Setmelanotide is indicated, this pathway is disrupted. Biallelic loss-of-function variants in the POMC, PCSK1, or LEPR genes interrupt the signaling cascade upstream of the MC4R.[4] These genetic defects result in deficient production or processing of POMC or an inability to respond to leptin signals, ultimately leading to insufficient α-MSH to activate the MC4R. The consequence of this impaired signaling is a state of constant, insatiable hunger (hyperphagia) and reduced energy expenditure, which drives severe, early-onset obesity.[5] Similarly, in Bardet-Biedl Syndrome (BBS), dysfunction of the BBSome protein complex impairs cilia function, which is critical for trafficking LEPR to the cell surface, thereby disrupting leptin signaling and downstream MC4R activation.[11]

Setmelanotide functions as a direct MC4R agonist, designed to pharmacologically bypass these upstream genetic blockades.[4] By binding to and activating the MC4R directly, Setmelanotide acts as a functional replacement for the missing endogenous α-MSH. This action restores downstream signaling in the pathway, re-establishing the physiological signals for satiety and energy balance. The result is a reduction in hyperphagia, decreased caloric intake, and subsequent weight loss.[4] This "bypass" mechanism is a sophisticated therapeutic strategy, validating a powerful concept in drug development for monogenic disorders where a pathway is disrupted at a specific point but downstream components remain functional.

3.2 Receptor Binding Profile and Selectivity

The clinical utility and safety profile of Setmelanotide are direct functions of its potency and selectivity at the MC4R relative to other members of the melanocortin receptor family.

• Potency at MC4R: Setmelanotide is a highly potent agonist of the human MC4R. In vitro assays measuring cyclic AMP (cAMP) production show that it activates the human MC4R with a half-maximal effective concentration (EC50​) of 0.27 nM.[4] This potency is approximately 20 times greater than that of the endogenous ligand, α-MSH, enabling robust receptor activation at therapeutic concentrations.[4]
• Selectivity Profile: The drug exhibits a distinct selectivity profile across the five known melanocortin receptors. Its functional activity profile is as follows: MC4 (EC50​ 0.27 nM) > MC3 (EC50​ 5.3 nM) ≈ MC1 (EC50​ 5.8 nM) > MC5 (EC50​ 1600 nM) ≟ MC2 (EC50​ >1000 nM).[1] This demonstrates a clear preference for the MC4R, with an approximately 19.6-fold selectivity over its next most active targets, the MC3R and MC1R.[1] This selectivity is crucial, as activation of different MC receptors mediates distinct physiological effects.
• Binding Mode: Setmelanotide's high affinity and specificity are further explained by its unique binding mode. It has been characterized as an "atypical bitopic ligand," meaning it interacts with both the primary (orthosteric) binding site and a secondary (putative allosteric) site on the MC4R.[4] This dual interaction likely contributes to its enhanced potency and stable receptor engagement.

The receptor selectivity profile directly predicts both the therapeutic efficacy and the key side effects of the drug. The high-potency agonism at MC4R is responsible for the desired effects on appetite and weight. Concurrently, the significant, albeit lower, agonist activity at the MC1R, which is a key regulator of melanocyte function and skin pigmentation, provides a clear pharmacological explanation for the common adverse effect of skin hyperpigmentation.[5] This is not a random off-target effect but a predictable consequence of the drug's inherent pharmacology.

3.3 Pharmacodynamic Effects

The activation of the MC4R by Setmelanotide translates into measurable physiological and metabolic effects that underpin its clinical efficacy.

• Appetite and Energy Expenditure: The primary pharmacodynamic effect of Setmelanotide is the suppression of appetite and the reversal of hyperphagia in patients with impaired MC4R pathway signaling.[5] This is achieved through its action on MC4Rs in key hypothalamic areas involved in appetite regulation, such as the paraventricular nucleus (PVN) and the lateral hypothalamic area (LHA).[1] In addition to reducing appetite, Setmelanotide has been shown to increase resting energy expenditure in both preclinical models and obese humans, providing a dual mechanism for promoting weight loss.[1]
• Cardiovascular Safety: A critical pharmacodynamic feature that distinguishes Setmelanotide from failed first-generation MC4R agonists (e.g., LY-2112688) is its favorable cardiovascular safety profile. Unlike its predecessors, whose development was halted due to concerning increases in heart rate and blood pressure, Setmelanotide has not been found to produce these adverse cardiovascular effects.[1] This superior safety profile was a pivotal factor in its successful clinical development, indicating that its specific chemical structure and binding mode allow for selective activation of satiety pathways without engaging those that lead to adverse cardiovascular stimulation. This positions Setmelanotide not merely as the first successful MC4R agonist, but as a second-generation success that overcame the key liability of its forerunners.
• Metabolic Improvements: Beyond weight management, Setmelanotide treatment has been associated with beneficial effects on metabolic health. In preclinical models, chronic administration was linked to significantly lower levels of serum glucose and improved insulin sensitivity, as measured by HOMA-IR values.[18] Clinical trials in humans have also reported improvements in metabolic parameters like lipid and fasting glucose levels, which often accompany weight loss.[5]

4.0 Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME) Profile

The pharmacokinetic profile of Setmelanotide describes its movement through and processing by the body, which dictates its dosing regimen and potential for drug interactions. Its properties are well-suited for a chronic, subcutaneously administered peptide therapeutic.[4]

• Absorption: Following subcutaneous injection, Setmelanotide is absorbed into the systemic circulation, reaching its maximum plasma concentration (Tmax​) in approximately 8 hours.[4] With once-daily administration, steady-state plasma concentrations are achieved within two days.[7]
• Distribution: The apparent volume of distribution (Vd​) of Setmelanotide is 48.7 L, indicating that the drug distributes into tissues beyond the plasma volume.[4] It exhibits moderate binding to plasma proteins, with a bound fraction of 79.1%.[4]
• Metabolism: As a peptide-based drug, Setmelanotide is not primarily metabolized by the hepatic cytochrome P450 (CYP450) enzyme system, which is the major pathway for most small-molecule drugs. Instead, it is expected to be broken down through general catabolic pathways in various tissues into smaller, inactive peptides and its constituent amino acids.[4] This metabolic profile confers a significant advantage by minimizing the potential for pharmacokinetic drug-drug interactions (DDIs), a crucial consideration for patients who may be on multiple medications for obesity-related comorbidities.[6]
• Excretion: Setmelanotide is cleared from the body with an elimination half-life (t1/2​) of approximately 11 hours.[4] This relatively long half-life for a peptide therapeutic supports a convenient once-daily dosing schedule. The drug's chemical design, incorporating a cyclic structure and D-amino acids, likely confers resistance to proteolytic degradation, thereby prolonging its circulation time and contributing to this favorable pharmacokinetic profile. Total clearance is estimated to be 4.86 L/hr.[4] A portion of the drug is excreted unchanged, with approximately 39% of a 3 mg subcutaneous dose being eliminated in the urine as the parent compound.[4]

5.0 Clinical Efficacy and Pivotal Trial Analysis

The clinical development program for Setmelanotide has robustly established its efficacy in patient populations with specific genetic obesities, leading to multiple regulatory approvals and ongoing investigations into new indications.

5.1 Efficacy in POMC, PCSK1, and LEPR Deficiency Obesities

The initial FDA approval of Setmelanotide was based on the results of two pivotal, multicenter, single-arm, open-label Phase 3 trials conducted between 2017 and 2018.[12] These trials enrolled patients aged 6 years and older with genetically confirmed, rare forms of obesity. One trial included 10 participants with obesity due to POMC or PCSK1 deficiency, while the second trial enrolled 11 participants with obesity due to LEPR deficiency.[1]

The primary efficacy endpoint for both trials was the proportion of patients who achieved a weight loss of 10% or more from baseline after one year of treatment.[1] The results were statistically significant and clinically meaningful:

• In the POMC/PCSK1 deficiency cohort, 8 out of 10 patients (80%) met the primary endpoint.[3]
• In the LEPR deficiency cohort, 5 out of 11 patients (45.5%) met the primary endpoint.[3]

A key secondary endpoint focused on the reduction of hyperphagia, as measured by patient-reported hunger scores. Significant improvements were observed:

• In the POMC/PCSK1 cohort, 50% of patients achieved at least a 25% reduction in their hunger scores.[13]
• In the LEPR cohort, 73% of patients achieved at least a 25% reduction in their hunger scores.[13]

The marked difference in weight loss response rates between the POMC/PCSK1 cohort (80%) and the LEPR cohort (45.5%) is a notable finding. While both conditions involve upstream disruption of the MC4R pathway, the differential response to the same downstream agonist suggests that the pathophysiology of LEPR deficiency may be more complex or less completely rescued by MC4R agonism alone. This may indicate the involvement of other leptin-dependent signaling pathways not addressed by Setmelanotide, highlighting that the specific genetic lesion has a significant impact on therapeutic outcomes.

5.2 Efficacy in Bardet-Biedl Syndrome (BBS)

Following its initial approval, Setmelanotide was evaluated for the treatment of obesity and hyperphagia in patients with Bardet-Biedl Syndrome (BBS), leading to a label expansion. The approval was supported by a pivotal Phase 3 clinical trial, which was the largest and longest interventional study conducted in this patient population to date.[26]

The trial successfully met its primary endpoint and all key secondary endpoints, demonstrating statistically significant and sustained reductions in both weight and hunger at 52 weeks of therapy.[26] Analysis of the data showed that approximately 36% of patients aged 12 years and older achieved at least a 10% reduction in body weight after one year.[13] A separate analysis across 44 participants found an average reduction in Body Mass Index (BMI) of 7.9%.[12] These results confirmed the efficacy of Setmelanotide in another distinct genetic disorder characterized by MC4R pathway impairment.

5.3 Investigational and Discontinued Indications

The clinical development of Setmelanotide extends beyond its currently approved indications, exploring its potential in other conditions and defining the boundaries of its efficacy.

• Hypothalamic Injury-induced Obesity (HIO): A significant strategic evolution for Setmelanotide is its investigation in HIO, an acquired condition resulting from physical damage to the hypothalamus (e.g., from a tumor or surgery) that disrupts the MC4R pathway.[27] The global, randomized, double-blind, placebo-controlled Phase 3 TRANSCEND trial evaluated Setmelanotide in 120 patients with HIO.[28] Topline results were highly positive, showing a statistically significant and clinically meaningful placebo-adjusted BMI reduction of -19.8% at 52 weeks.[30] Based on these robust data, supplemental regulatory applications have been submitted to and accepted by the FDA and EMA for this indication.[28] This potential expansion from treating monogenic diseases to an acquired form of pathway dysfunction could significantly broaden the drug's therapeutic utility.
• Prader-Willi Syndrome (PWS): Setmelanotide was investigated in a Phase 2 trial for PWS, another genetic disorder characterized by severe hyperphagia and obesity, which was hypothesized to involve MC4R pathway deficiency.[1] However, preliminary data from this trial showed no clinical benefit.[1] This negative result is highly informative, as it helps to define the mechanistic boundaries of the drug. It strongly suggests that the pathophysiology of hyperphagia in PWS is not primarily driven by a simple deficiency in MC4R signaling that is correctable by an agonist, but likely involves more complex neurobiological mechanisms.
• Other Genetic Variants: The DAYBREAK Phase 2 study was designed to evaluate Setmelanotide in a broader group of participants with obesity and specific gene variants within the MC4R pathway, reflecting ongoing efforts to identify other responsive patient populations.[34]

Table 5.1: Summary of Efficacy from Pivotal Phase 3 Trials

Indication	Number of Patients	Primary Endpoint (% of Patients with ≥10% Weight Loss at 1 Year)	Key Secondary Endpoint (% of Patients with ≥25% Reduction in Hunger Score)
POMC/PCSK1 Deficiency	10	80%	50%
LEPR Deficiency	11	45.5%	73%
Bardet-Biedl Syndrome (BBS)	28 (≥12 years)	~36%	Statistically Significant Reduction

6.0 Safety and Tolerability Profile

The safety and tolerability of Setmelanotide have been extensively characterized through its clinical trial program and post-marketing experience. The adverse event profile is generally manageable, with several notable effects directly related to its mechanism of action.

6.1 Common and Serious Adverse Events

The most frequently observed adverse events (AEs) are consistent across the different patient populations studied, though incidences can vary.

• Most Common AEs (>10%): The most common side effects reported in clinical trials include injection site reactions (e.g., pain, erythema, pruritus), skin hyperpigmentation, nausea, headache, diarrhea, abdominal pain, and vomiting.[1] The incidence of these events can differ by patient cohort, as detailed in Table 6.1.
• Serious AEs: While less common, serious adverse events have been reported. These include hypersensitivity reactions, such as anaphylaxis, which have been observed in post-marketing reports.[2] Additionally, depression and suicidal ideation are identified as serious risks requiring careful monitoring.[1]

Table 6.1: Adverse Events Reported in Clinical Trials (≥10% Incidence)

Adverse Event	Incidence in POMC/PCSK1/LEPR Deficiency (Aged ≥6)	Incidence in BBS (Aged ≥6)	Incidence in Pediatric Patients (Aged 2-6)
Injection Site Reaction	96%	51%	67%
Skin Hyperpigmentation	78%	63%	83%
Nausea	56%	26%	Not specified ≥10%
Headache	41%	7%	Not specified ≥10%
Diarrhea	37%	14%	25%
Abdominal Pain	33%	Not specified ≥10%	Not specified ≥10%
Back Pain	33%	Not specified ≥10%	Not specified ≥10%
Fatigue	30%	5%	Not specified ≥10%
Vomiting	30%	19%	58%
Depression	26%	Not specified ≥10%	Not specified ≥10%
Upper Respiratory Tract Infection	26%	Not specified ≥10%	33%
Spontaneous Penile Erections	23%	25%	Not specified ≥10%
Melanocytic Nevus	19%	14%	33%
Suicidal Ideation	11%	Not specified ≥10%	Not specified ≥10%

Source: Data compiled from Medscape [7]

6.2 Warnings and Precautions

The prescribing information for Imcivree includes several important warnings and precautions to guide its safe use.

• Disturbances in Sexual Arousal: Setmelanotide treatment has been associated with spontaneous penile erections in males and unwanted sexual reactions (e.g., changes in sexual arousal without sexual activity) in females. Patients should be counseled on this potential side effect, and males are advised to seek immediate emergency medical attention for any erection lasting longer than 4 hours.[1]
• Depression and Suicidal Ideation: Cases of depression, depressed mood, and suicidal ideation have been reported in patients treated with Setmelanotide. It is crucial for healthcare providers to monitor patients for the new onset or worsening of these symptoms. Discontinuation of the drug should be considered if patients experience suicidal thoughts or behaviors or clinically significant depression.[1]
• Benzyl Alcohol Toxicity: The Imcivree solution contains benzyl alcohol as a preservative. Benzyl alcohol can cause serious and potentially fatal adverse reactions, including "gasping syndrome," in neonates and low-birth-weight infants. Consequently, Imcivree is not approved for and must not be used in this vulnerable population.[2]

6.3 Mechanism-Related Effects

Certain adverse effects are a direct pharmacological consequence of Setmelanotide's interaction with the melanocortin receptor system.

• Skin Hyperpigmentation and Nevi Changes: The most prominent mechanism-related side effect is increased skin pigmentation. This occurs due to the drug's agonist activity at the MC1R, which regulates melanin production in the skin. This can manifest as generalized or focal skin darkening, darkening of pre-existing moles (nevi), and the development of new nevi. These changes are considered a pharmacological effect of the drug and are reversible upon discontinuation. It is recommended that patients undergo a full-body skin examination before initiating therapy and periodically during treatment to monitor for any changes in pigmentary lesions.[2]

6.4 Contraindications and Drug Interactions

• Contraindications: The only absolute contraindication for Imcivree is a history of a serious hypersensitivity reaction (e.g., anaphylaxis) to Setmelanotide or any of the excipients in the formulation.[2] Due to the potential for harm to a developing fetus from maternal weight loss, it is also recommended that treatment be discontinued if a patient becomes pregnant, unless the potential benefits are deemed to outweigh the risks.[6]
• Drug Interactions: Setmelanotide has a low potential for engaging in pharmacokinetic drug-drug interactions. Its metabolism via general catabolic pathways rather than the CYP450 enzyme system means it is unlikely to affect or be affected by drugs that are inhibitors or inducers of these enzymes.[6]

7.0 Regulatory Landscape and Approval History

Setmelanotide's path to approval was accelerated by multiple special regulatory designations from global health authorities, reflecting the significant unmet medical need for treatments for rare genetic diseases of obesity.

• Special Designations: In the United States, the Food and Drug Administration (FDA) granted Setmelanotide Orphan Drug Designation, Breakthrough Therapy Designation, and Rare Pediatric Disease Designation.[3] In Europe, the European Medicines Agency (EMA) granted it PRIority MEdicines (PRIME) status and Orphan Designation for its initial indications, facilitating enhanced regulatory support and dialogue.[13]

The global approval timeline demonstrates a strategic, stepwise expansion of indications and patient populations.

• U.S. FDA Approval Timeline:
• November 25, 2020: The FDA granted initial approval to Imcivree for chronic weight management in adult and pediatric patients aged 6 years and older with obesity due to genetically confirmed POMC, PCSK1, or LEPR deficiency.[1]
• June 16, 2022: The FDA approved a supplemental New Drug Application (sNDA), expanding the indication to include chronic weight management in patients aged 6 years and older with Bardet-Biedl Syndrome (BBS).[12]
• December 20, 2024: The indication was further expanded to include children as young as 2 years of age for all previously approved conditions (POMC, PCSK1, LEPR deficiencies, and BBS).[8]
• Pending (PDUFA Date Dec 20, 2025): The FDA has accepted an sNDA for the treatment of acquired hypothalamic obesity (HIO) and has granted it Priority Review, signifying its potential to provide a significant improvement in the treatment of a serious condition.[28]
• European EMA Approval Timeline:
• July 2021: The European Commission (EC) granted marketing authorization for Imcivree for the treatment of obesity and control of hunger in patients aged 6 years and older with genetically confirmed loss-of-function biallelic POMC, PCSK1, or LEPR deficiency.[1] This was later expanded to include BBS.
• July 31, 2024: The marketing authorization was expanded to lower the age limit, including children between 2 and 6 years old for all approved indications.[44]
• Pending: A Type II variation to the Marketing Authorization Application (MAA) for the HIO indication is currently under review by the EMA's Committee for Medicinal Products for Human Use (CHMP).[28]
• Other Regions: The UK's Medicines & Healthcare products Regulatory Agency (MHRA) has authorized Setmelanotide, with its timeline closely mirroring the EMA's, including the 2022 approval for patients ≥6 years and the 2024 expansion to patients ≥2 years.[36] Health Canada approved the medication on May 4, 2023.[4]

Table 7.1: Global Regulatory Milestones for Setmelanotide (Imcivree®)

Date	Regulatory Agency	Action	Indication / Population
July 14, 2016	EMA	Orphan Designation	POMC deficiency
Nov 19, 2018	EMA	Orphan Designation	LEPR deficiency
Aug 21, 2019	EMA	Orphan Designation	Bardet-Biedl syndrome
Nov 25, 2020	FDA	Initial Approval	POMC, PCSK1, LEPR deficiency (≥6 years)
July 23, 2021	EMA	Marketing Authorization	POMC, PCSK1, LEPR deficiency (≥6 years)
June 16, 2022	FDA	Label Expansion	Bardet-Biedl syndrome (≥6 years)
May 4, 2023	Health Canada	Approval	POMC, PCSK1, LEPR deficiency, BBS
July 31, 2024	EMA	Label Expansion	All approved indications (≥2 years)
Dec 20, 2024	FDA	Label Expansion	All approved indications (≥2 years)
Aug 16, 2025	EMA	MAA Review Started	Acquired Hypothalamic Obesity (HIO)
Dec 20, 2025 (PDUFA)	FDA	sNDA Under Review	Acquired Hypothalamic Obesity (HIO)

8.0 Dosing, Administration, and Patient Management

The clinical application of Setmelanotide requires careful patient selection, appropriate dosing and administration, and diligent monitoring for both efficacy and safety.

8.1 Dosage and Administration

Imcivree is supplied as a 10 mg/mL solution in a multiple-dose vial for subcutaneous injection. It is administered once daily, at approximately the same time each day, with or without food.[5] Patients or their caregivers can be trained to prepare and administer the injection at home.[2]

The dosing regimen is tailored based on age and is titrated to achieve an optimal balance of efficacy and tolerability.

• Adults (18 years of age and older): The recommended starting dose is 2 mg injected subcutaneously once daily for the first two weeks. Based on the patient's response and tolerability, the dose may be increased to the target maintenance dose of 3 mg once daily. If the initial dose is not well tolerated, it can be reduced to 1 mg daily.[5]
• Pediatric Patients (2 to <18 years of age): For pediatric patients, the recommended starting dose is lower. For children aged 6 to <12 years, the starting dose is 1 mg daily for two weeks, with titration based on response.[5] The prescribing information provides specific titration schedules for different pediatric age groups.[24]

8.2 Patient Management

Effective and safe use of Setmelanotide involves several key management steps before and during therapy.

• Genetic Testing: A critical prerequisite for initiating therapy in patients with suspected monogenic obesity is genetic testing. An FDA-approved test is required to confirm the presence of pathogenic, likely pathogenic, or variants of uncertain significance (VUS) in the POMC, PCSK1, or LEPR genes. The drug is not indicated for patients whose variants are classified as benign or likely benign.[2]
• Monitoring for Efficacy: The therapeutic response to Setmelanotide should be assessed periodically. The label provides guidance on discontinuing treatment in non-responders. For patients with POMC, PCSK1, or LEPR deficiency, if a clinically meaningful amount of weight is not lost after 3 to 4 months of treatment, it is unlikely they will benefit from continued therapy. For patients with BBS, this assessment period is extended to one year. In such cases, the physician may recommend stopping the medication.[15]
• Monitoring for Safety: Proactive safety monitoring is essential. This includes:
• Skin Examinations: A full-body skin examination should be performed before starting treatment and periodically thereafter to monitor for any changes in skin pigmentation or nevi.[2]
• Mental Health: Patients and caregivers should be counseled on the risk of depression and suicidal ideation and instructed to report any new or worsening symptoms immediately.[2]
• Cardiovascular Monitoring: In Europe, the EMA recommends that heart rate and blood pressure be monitored at each medical visit (at least every 6 months) as part of standard clinical practice for patients treated with Setmelanotide.[36]

9.0 Synthesis and Future Directions

Setmelanotide (Imcivree®) stands as a landmark achievement in the field of obesity medicine, representing a paradigm shift away from generalized treatments and toward a genetically stratified, precision approach. Its development and approval validate the MC4R pathway as a critical and druggable target for conditions of severe obesity driven by specific molecular deficits. By directly addressing the root cause of hyperphagia and weight gain in select patient populations, Setmelanotide has demonstrated a level of efficacy that is rarely seen with traditional anti-obesity agents in these individuals. It is crucial to recognize that its mechanism is highly specific; it is a targeted therapy for defined MC4R pathway defects and is not a treatment for the far more common condition of general (polygenic) obesity.[1]

The success of Setmelanotide has established a new precedent in the management of severe obesity, underscoring the concept that obesity is not a single, homogenous entity but rather a collection of distinct diseases, some of which have a treatable monogenic basis. This will inevitably catalyze a greater emphasis on genetic testing in the diagnosis and management of patients with severe, early-onset obesity, allowing for the identification of individuals who may benefit from this targeted therapy.

Looking forward, the most significant evolution for Setmelanotide is its potential expansion into the treatment of Acquired Hypothalamic Obesity (HIO). A potential approval in this indication would move the drug beyond the realm of congenital genetic diseases into treating an acquired form of MC4R pathway dysfunction caused by physical injury. This would not only broaden the drug's utility to a new patient population but also reinforce the central importance of the MC4R pathway in weight regulation, regardless of whether its impairment is congenital or acquired. Further research into other rare genetic disorders associated with this pathway, such as Alström syndrome and various heterozygous deficiencies, may also yield future label expansions.[12] The continued investment by Rhythm Pharmaceuticals in next-generation MC4R agonists, such as LB54640 and RM-718, signals a long-term strategic commitment to leveraging this biological pathway to address rare neuroendocrine and metabolic diseases.[36]

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