Melanocortin 4 receptor agonists for the treatment of obesity represent a highly targeted therapeutic approach for rare genetic forms of severe obesity. Unlike conventional weight-loss medicines, these agents work by restoring impaired signalling in the melanocortin pathway—a critical system in the brain that regulates appetite and energy balance. In the UK, setmelanotide is the only licensed MC4R agonist, approved exclusively for patients with genetically confirmed deficiencies such as POMC, PCSK1, or LEPR deficiency, or clinically diagnosed Bardet–Biedl syndrome. This precision medicine is not indicated for common obesity and is prescribed only through specialist centres within highly specialised NHS services.

What Are Melanocortin 4 Receptor Agonists?

Melanocortin 4 receptor (MC4R) agonists are a class of medicines developed to treat certain rare forms of obesity by targeting specific pathways in the brain that regulate appetite and energy balance. These medicines work by mimicking the action of naturally occurring hormones that bind to melanocortin 4 receptors, which are found in the hypothalamus and other areas of the central nervous system involved in controlling hunger, satiety, and metabolic processes.

The melanocortin system plays a fundamental role in body weight regulation. When functioning normally, activation of MC4R receptors helps to suppress appetite and may influence energy expenditure. However, genetic mutations affecting this receptor or its signalling pathway can lead to severe early-onset obesity, often accompanied by insatiable hunger (hyperphagia). Conditions such as pro-opiomelanocortin (POMC) deficiency, proprotein convertase subtilisin/kexin type 1 (PCSK1) deficiency, leptin receptor (LEPR) deficiency, and Bardet–Biedl syndrome (BBS) involve impaired melanocortin signalling.

MC4R agonists have been developed specifically to address deficiencies in this pathway, offering a targeted therapeutic approach for these rare genetic forms of obesity. Unlike other weight-loss medicines that work through various mechanisms, MC4R agonists are designed to restore or enhance a specific biological pathway that is impaired in these conditions. It is important to note that MC4R agonists are not licensed or recommended for common (polygenic) obesity, which accounts for the vast majority of obesity cases in the UK. Outside the licensed indications, use of MC4R agonists remains investigational.

How MC4R Agonists Work to Reduce Body Weight

MC4R agonists exert their weight-reducing effects primarily through their action on appetite regulation in the central nervous system. When these medicines bind to melanocortin 4 receptors in the hypothalamus, they activate intracellular signalling pathways that influence feeding behaviour and hunger.

The main mechanism involves appetite suppression and reduction of hyperphagia. By activating MC4R receptors, these agonists enhance satiety signals and reduce hunger sensations, leading to decreased food intake. Patients typically report feeling fuller more quickly during meals and experiencing reduced cravings and insatiable hunger between meals. This effect on appetite regulation occurs through the modulation of neuropeptides involved in feeding behaviour, including pro-opiomelanocortin (POMC) derivatives that naturally activate these receptors.

Whilst MC4R activation may also influence energy expenditure and thermogenesis (the production of heat by the body), the evidence for this effect in humans is limited, and appetite suppression remains the primary established mechanism of action. Some studies have suggested potential effects on glucose metabolism, though these findings require further investigation and should be considered exploratory.

Setmelanotide, the currently licensed MC4R agonist, is administered as a once-daily subcutaneous injection. Dosing is initiated at a low level and gradually increased (titrated) based on individual clinical response and tolerability, as outlined in the Summary of Product Characteristics (SmPC). The aim is to achieve meaningful reductions in hunger and body weight whilst managing potential side effects.

Licensed MC4R Agonists for Obesity in the UK

In the United Kingdom, setmelanotide (Imcivree) is currently the only MC4R agonist licensed by the Medicines and Healthcare products Regulatory Agency (MHRA) for the treatment of obesity. Setmelanotide received regulatory approval for highly specific indications involving genetically confirmed or clinically diagnosed deficiencies in the leptin-melanocortin pathway.

The licensed indications for setmelanotide include patients aged six years and older with obesity and the control of hunger due to:

• Pro-opiomelanocortin (POMC) deficiency – confirmed by the presence of pathogenic or likely pathogenic loss-of-function variants in the POMC gene

• Proprotein convertase subtilisin/kexin type 1 (PCSK1) deficiency – confirmed by the presence of pathogenic or likely pathogenic loss-of-function variants in the PCSK1 gene

• Leptin receptor (LEPR) deficiency – confirmed by the presence of pathogenic or likely pathogenic loss-of-function variants in the LEPR gene

• Bardet–Biedl syndrome (BBS) – as diagnosed by a specialist physician, often with genetic confirmation where available

These rare genetic conditions result in impaired melanocortin signalling, leading to severe early-onset obesity, insatiable hunger, and, in the case of BBS, additional features such as retinal dystrophy, polydactyly, renal abnormalities, and hypogonadism. Setmelanotide is administered as a once-daily subcutaneous injection, and for POMC, PCSK1, and LEPR deficiencies, genetic confirmation of the relevant mutations is required before treatment initiation.

The availability of setmelanotide through the NHS is subject to specific commissioning arrangements, typically managed through highly specialised services for rare diseases. Access requires referral to specialist centres with expertise in genetic obesity syndromes, where comprehensive genetic testing (where applicable) and multidisciplinary assessment can be undertaken. The National Institute for Health and Care Excellence (NICE) has evaluated setmelanotide within its highly specialised technologies programme for Bardet–Biedl syndrome, and NHS England has established commissioning pathways for eligible patients. It is important to emphasise that setmelanotide is not licensed or recommended for common polygenic obesity.

Effectiveness and Clinical Trial Evidence

Clinical trial evidence for setmelanotide has demonstrated efficacy in patients with confirmed genetic deficiencies affecting the melanocortin pathway, though it is important to note that the evidence comes from small, single-arm, open-label studies with inherent limitations.

In patients with POMC or PCSK1 deficiency, clinical trials reported that approximately 80% of participants achieved at least 10% body weight reduction after one year of treatment. Mean weight loss in these studies exceeded 25% in some cases, with participants also reporting substantial reductions in hunger scores. These results are notable given that this patient population had previously shown minimal response to conventional weight management interventions, including dietary modification, behavioural therapy, and other pharmacological treatments.

For individuals with LEPR deficiency, the response to setmelanotide was more variable. In pivotal studies, approximately half of participants achieved clinically meaningful weight loss, with reductions in hunger also observed. The degree of response in LEPR deficiency appears to be lower than that seen in POMC or PCSK1 deficiency.

In patients with Bardet–Biedl syndrome, setmelanotide treatment resulted in modest mean weight loss, with more marked improvements in hunger scores. The clinical benefit in this population includes both weight reduction and improved control of hyperphagia, which can significantly affect quality of life.

Long-term extension studies have shown that weight loss and hunger control can be maintained with continued treatment over periods extending beyond two years. However, discontinuation of treatment typically results in weight regain, indicating that ongoing therapy is necessary to maintain benefits. Some exploratory data suggest potential improvements in metabolic markers such as glycaemic control, though these findings require further investigation.

It is essential to emphasise that these results apply specifically to patients with confirmed genetic deficiencies or clinically diagnosed Bardet–Biedl syndrome. There is currently no evidence supporting the effectiveness of MC4R agonists in common obesity without these specific genetic or syndromic features, and such use is not recommended. The response seen in rare genetic obesity syndromes highlights the importance of precision medicine approaches in obesity treatment.

References: MHRA/emc Summary of Product Characteristics for setmelanotide (Imcivree); European Medicines Agency (EMA) European Public Assessment Report (EPAR) for setmelanotide; NICE Highly Specialised Technologies guidance on setmelanotide for Bardet–Biedl syndrome.

Side Effects and Safety Considerations

As with all medicines, MC4R agonists are associated with potential adverse effects that require careful monitoring and patient education. Understanding these side effects is essential for both healthcare professionals and patients to ensure safe and effective treatment.

Common adverse effects of setmelanotide include:

• Skin hyperpigmentation and darkening of pre-existing moles (naevi): This is the most frequently reported side effect, occurring in the majority of patients. It results from the medicine's activity on melanocortin 1 receptors in the skin. Patients should have a baseline skin examination before starting treatment and periodic skin checks during treatment to monitor for new or changing moles. General sun protection measures are advised.

• Injection site reactions: Pain, redness, itching, or swelling at injection sites are common, particularly during initial treatment. Rotating injection sites and using proper injection technique can help minimise these reactions.

• Nausea and vomiting: Gastrointestinal side effects may occur, especially when initiating treatment or increasing doses. These effects often diminish with continued use.

• Diarrhoea: Loose stools or diarrhoea have been reported.

• Headache: Headaches are a commonly reported side effect.

• Fatigue: Some patients experience tiredness or fatigue.

• Spontaneous penile erections and increased sexual arousal: These adverse effects, resulting from melanocortin receptor activation, have been reported in male and female patients and can be distressing. Patients should be informed of this possibility before starting treatment. Male patients experiencing an erection lasting longer than four hours should seek urgent medical attention, as prolonged erections (priapism) require prompt treatment.

Serious safety considerations include the potential for depression and suicidal ideation, though a direct causal link has not been definitively established. Patients and caregivers should be advised to monitor for mood changes and seek immediate medical attention if concerning symptoms develop.

Setmelanotide is subject to additional monitoring in Great Britain (indicated by a black triangle ▼), meaning that all suspected adverse reactions should be reported. You can report suspected side effects via the MHRA Yellow Card scheme at yellowcard.mhra.gov.uk or by downloading the Yellow Card app. Reporting helps ensure the ongoing safety of this medicine.

Regular monitoring is essential during treatment, including assessment of weight, hunger, metabolic parameters, skin changes (including new or changing moles), and psychological wellbeing. Patients should be advised to report any new or worsening symptoms promptly to their healthcare team. The benefits of treatment must be carefully weighed against potential risks on an individual basis, with ongoing reassessment throughout the treatment course.

References: MHRA/emc Summary of Product Characteristics for setmelanotide (Imcivree); EMA European Public Assessment Report (EPAR) for setmelanotide; MHRA Yellow Card scheme (yellowcard.mhra.gov.uk).

Who Can Be Prescribed MC4R Agonists for Obesity?

Prescription of MC4R agonists in the UK is highly restricted and reserved for a very specific patient population. Unlike other obesity medicines that may be prescribed more broadly, setmelanotide is indicated exclusively for patients with genetically confirmed deficiencies in the leptin-melanocortin pathway or clinically diagnosed Bardet–Biedl syndrome.

Eligibility criteria for setmelanotide treatment include:

• Confirmed genetic diagnosis (for POMC, PCSK1, or LEPR deficiency): Patients must have documented pathogenic or likely pathogenic loss-of-function variants in the relevant genes, confirmed through genetic testing at an accredited laboratory.

• Clinical diagnosis of Bardet–Biedl syndrome: Diagnosis is made by a specialist physician, often supported by genetic testing where available. BBS is characterised by features such as retinal dystrophy, polydactyly, renal abnormalities, hypogonadism, and early-onset obesity with hyperphagia.

• Age requirement: Treatment is licensed for patients aged six years and older, including children, adolescents, and adults.

• Clinical phenotype: Patients with POMC, PCSK1, or LEPR deficiency typically present with severe early-onset obesity (often before age five years), insatiable hunger (hyperphagia), and may have additional features such as red hair (in POMC deficiency) or endocrine abnormalities.

The prescribing pathway requires referral to specialist centres with expertise in genetic obesity syndromes and rare diseases. These centres, typically part of highly specialised services commissioned by NHS England, can arrange appropriate genetic testing (where applicable), confirm eligibility, and provide the multidisciplinary support necessary for optimal treatment outcomes. Genetic counselling should be offered to patients and families to discuss the implications of genetic findings.

Red flags prompting referral to a highly specialised genetic obesity service include:

• Severe early-onset obesity (typically before age five years)

• Marked, insatiable hunger (hyperphagia) that is difficult to control

• Family history of early-onset severe obesity

• Syndromic features suggestive of Bardet–Biedl syndrome, such as polydactyly (extra fingers or toes), retinal dystrophy or visual impairment, renal anomalies, or hypogonadism

If you or your child have these features, discuss with your GP whether referral to a specialist service might be appropriate.

Contraindications and precautions must be carefully considered. Setmelanotide should not be used in patients with hypersensitivity to the active substance or any of the excipients. Caution is advised in patients with a history of depression or suicidal ideation. The medicine should be avoided during pregnancy unless the potential benefit justifies the potential risk to the foetus. Women should not breastfeed during treatment with setmelanotide and for a period after the last dose, as specified in the SmPC.

It is crucial to emphasise that MC4R agonists are not appropriate for common (polygenic) obesity without confirmed genetic deficiencies or Bardet–Biedl syndrome. Patients with common obesity should be managed according to standard NICE guidance, which recommends a tiered approach including lifestyle interventions, behavioural support, and, where appropriate, other licensed anti-obesity medicines or bariatric surgery.

References: MHRA/emc Summary of Product Characteristics for setmelanotide (Imcivree); NICE Highly Specialised Technologies guidance on setmelanotide for Bardet–Biedl syndrome; NHS England specialised commissioning policies for rare genetic obesity; NICE guidance on obesity management (NG28, CG189).

Frequently Asked Questions