Once-monthly maridebart cafraglutide (AMG 133) is an investigational obesity treatment combining a GLP-1 receptor agonist with a GIP receptor antagonist in a single monthly injection. This dual-mechanism approach targets appetite regulation, gastric emptying, and metabolic pathways involved in weight management. Whilst early clinical trials have shown promising weight loss results, maridebart cafraglutide has not yet received marketing authorisation from the MHRA or European Commission and remains unavailable for prescription use in the UK. This article examines the medicine's mechanism of action, emerging clinical evidence, potential eligibility criteria, safety considerations, and the regulatory pathway required before NHS access becomes possible.

What Is Maridebart Cafraglutide and How Does It Work?

Maridebart cafraglutide (also known as AMG 133) is an investigational medicine for obesity management that combines two distinct therapeutic mechanisms in a single once-monthly injectable formulation. This medicine is designed to address the complex metabolic and hormonal factors that contribute to obesity and weight regulation.

The compound consists of two active components working together. The first component is a glucagon-like peptide-1 (GLP-1) receptor agonist, similar to other medicines in this class such as semaglutide and liraglutide. GLP-1 agonists work by mimicking a naturally occurring hormone that regulates appetite and food intake. They slow gastric emptying, enhance feelings of fullness after meals, and reduce hunger signals in the brain. The second component is a monoclonal antibody that antagonises the glucose-dependent insulinotropic polypeptide (GIP) receptor, targeting specific pathways involved in energy balance and metabolism.

Key mechanisms of action include:

• Appetite suppression through central nervous system pathways that regulate hunger and satiety

• Delayed gastric emptying, which prolongs the sensation of fullness after eating

• Improved glucose metabolism and insulin sensitivity, which may benefit individuals with obesity-related metabolic complications

• GIP receptor antagonism, which may influence fat metabolism and energy storage

The once-monthly dosing schedule is achieved through the extended half-life of the antibody–peptide construct, which may improve convenience and adherence compared with current weekly injectable obesity treatments. However, it is important to note that maridebart cafraglutide remains under clinical investigation and is not yet authorised by the MHRA or the European Commission (following EMA assessment) for use in the UK or Europe.

Clinical Evidence for Once-Monthly Maridebart Cafraglutide in Obesity

As an investigational therapy, maridebart cafraglutide is currently undergoing clinical trials to establish its efficacy and safety profile for obesity treatment. The available evidence comes primarily from early-phase clinical studies, which are designed to evaluate weight loss outcomes, metabolic benefits, and safety parameters.

Preliminary data from early-phase trials have suggested promising weight reduction results. Participants receiving maridebart cafraglutide demonstrated statistically significant weight loss compared to placebo groups in these studies. However, comprehensive peer-reviewed publications of efficacy data are still awaited, and the full magnitude and durability of weight loss remain to be established.

Key clinical trial endpoints being evaluated include:

• Primary outcome: Percentage change in body weight from baseline

• Secondary outcomes: Proportion of participants achieving ≥5%, ≥10%, and ≥15% weight loss

• Metabolic parameters: Changes in HbA1c, fasting glucose, lipid profiles, and blood pressure

• Quality of life measures and patient-reported outcomes

It is important to emphasise that comprehensive long-term trial data are still being collected and analysed. Long-term efficacy beyond 12 months, cardiovascular outcomes, and durability of weight loss after treatment discontinuation remain areas requiring further investigation. The full clinical evidence package will be essential for regulatory review by the MHRA and the European Commission (following EMA assessment) before any potential authorisation for use in the UK. Healthcare professionals and patients should await peer-reviewed publication of complete trial results before drawing conclusions about the medicine's place in obesity therapy. Direct comparisons with existing GLP-1 receptor agonist therapies have not been conducted in head-to-head trials.

Who Might Be Eligible for Maridebart Cafraglutide if Approved?

As maridebart cafraglutide has not yet received marketing authorisation from the MHRA, it is not currently available for prescription use in the UK. However, based on the design of ongoing clinical trials and the established framework for obesity pharmacotherapy, we can anticipate the likely eligibility criteria that may apply if the medicine receives authorisation and subsequent NICE approval.

Current NICE Technology Appraisals for approved anti-obesity medicines (such as TA875 for semaglutide 2.4 mg and TA664 for liraglutide 3 mg) define specific eligibility criteria based on body mass index (BMI) thresholds, the presence of weight-related comorbidities, and prior engagement with lifestyle interventions. It is reasonable to expect that maridebart cafraglutide, if approved, would be subject to a similar NICE appraisal process to determine its place in UK obesity management.

Potential eligibility considerations may include:

• BMI thresholds: Adults with BMI ≥30 kg/m² or ≥27.5 kg/m² for people of South Asian, Chinese, other Asian, Middle Eastern, Black African or African-Caribbean family background (adjusted thresholds reflect higher metabolic risk at lower BMI in certain ethnic groups)

• Previous weight management attempts: Evidence of engagement with dietary modification, increased physical activity, and behavioural interventions through a specialist weight management service

• Absence of contraindications: Specific contraindications will be defined in the Summary of Product Characteristics (SmPC) if the medicine is authorised

• Commitment to lifestyle modification: Willingness to participate in a comprehensive weight management programme

Clinical trials have typically excluded individuals with recent cardiovascular events, severe renal or hepatic impairment, pregnancy or planned pregnancy, and those with a history of pancreatitis. The medicine would likely not be suitable for children and adolescents unless specific paediatric trials demonstrate safety and efficacy in younger populations. Any future NHS access would be determined by NICE guidance and local integrated care board (ICB) commissioning decisions. Patients interested in this treatment should discuss their individual circumstances with their GP or specialist weight management service once regulatory authorisation and NICE appraisal are completed.

Side Effects and Safety Considerations

While the complete safety profile of maridebart cafraglutide is still being established through ongoing clinical trials, the adverse effect profile appears consistent with the known class effects of GLP-1 receptor agonists, with some additional considerations related to its dual mechanism of action. The following information is based on class effects observed with approved GLP-1 receptor agonists and early trial data; product-specific safety information will be defined in the Summary of Product Characteristics (SmPC) if the medicine is authorised.

Gastrointestinal side effects are the most commonly reported adverse reactions with GLP-1 receptor agonists and have been observed in clinical trials of maridebart cafraglutide. These include:

• Nausea (typically most pronounced during dose escalation)

• Vomiting and diarrhoea

• Constipation

• Abdominal discomfort or pain

These gastrointestinal symptoms are generally mild to moderate in severity and tend to diminish over time as the body adapts to treatment. However, they represent the most common reason for treatment discontinuation in clinical trials of GLP-1 receptor agonists.

Other potential adverse effects observed with GLP-1 receptor agonists include:

• Injection site reactions: Redness, swelling, or discomfort at the injection site

• Fatigue and dizziness: Particularly during the initial treatment period

• Increased heart rate: A modest elevation in resting heart rate has been noted with GLP-1 agonists

• Hypoglycaemia: Risk is low when used alone but increases if combined with insulin or sulphonylureas

Serious safety considerations require careful monitoring. There is a potential risk of pancreatitis with GLP-1 receptor agonists. Patients should be advised to seek immediate medical attention if they experience severe, persistent abdominal pain. Additionally, thyroid C-cell tumours have been observed in rodent studies of GLP-1 receptor agonists; the relevance to humans is uncertain. Gallbladder disease, including cholelithiasis and cholecystitis, has been associated with rapid weight loss and GLP-1 agonist use.

When to contact your GP:

• Severe or persistent abdominal pain that may radiate to the back

• Signs of pancreatitis (severe nausea, vomiting, fever)

• Symptoms of gallbladder disease (right upper abdominal pain, jaundice)

• Persistent vomiting leading to dehydration

• Signs of allergic reaction (rash, difficulty breathing, facial swelling)

Pregnancy must be avoided during treatment, as the safety of maridebart cafraglutide in pregnancy has not been established. Women of childbearing potential should use effective contraception throughout treatment and for a specified period after discontinuation, as determined by the medicine's elimination half-life once this is fully characterised.

Reporting side effects: If you experience any side effects, talk to your doctor or pharmacist. You can also report suspected side effects directly via the Yellow Card scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects, you can help provide more information on the safety of medicines.

Accessing Treatment Through the NHS

Maridebart cafraglutide is not currently available through the NHS as it has not yet received marketing authorisation from the MHRA or the European Commission (following EMA assessment). The medicine remains in clinical development, and patients cannot access it outside of participation in approved clinical trials.

If maridebart cafraglutide successfully completes its clinical development programme and receives regulatory authorisation, there will be a subsequent evaluation process before it becomes available on the NHS. NICE will conduct a technology appraisal to assess the clinical effectiveness and cost-effectiveness of the treatment compared to existing obesity therapies. This appraisal considers the quality of clinical evidence, the magnitude of health benefits, the cost per quality-adjusted life year (QALY), and the budget impact on the NHS. NICE technology appraisals for currently approved anti-obesity medicines (such as TA875 for semaglutide 2.4 mg, TA664 for liraglutide 3 mg, and TA494 for naltrexone–bupropion) provide examples of how eligibility criteria, service settings, and stopping rules are determined.

The current pathway for accessing obesity pharmacotherapy through the NHS provides a framework for how maridebart cafraglutide might be accessed in future:

Step 1: Initial assessment – Patients should first consult their GP to discuss weight management options. The GP will assess BMI, identify weight-related comorbidities, and review previous weight loss attempts.

Step 2: Lifestyle intervention – NICE guidance recommends a trial of dietary modification, increased physical activity, and behavioural support before considering pharmacological treatment. Many areas have specialist weight management services (tier 3 services) that provide structured programmes.

Step 3: Pharmacological treatment consideration – If lifestyle interventions alone are insufficient and eligibility criteria are met, the GP or specialist service may prescribe approved anti-obesity medication. Currently available options include orlistat, naltrexone–bupropion, liraglutide 3 mg, and semaglutide 2.4 mg (where commissioned by local integrated care boards).

Step 4: Monitoring and review – Treatment response is assessed according to the specific NICE technology appraisal for each medicine. For example, NICE TA875 recommends continuing semaglutide 2.4 mg only if there is at least 5% weight loss at 6 months. Stopping rules are defined individually for each approved medicine.

Regional variation exists in NHS access to obesity treatments. Some integrated care boards (ICBs) have commissioned specialist tier 3 weight management services with access to the full range of NICE-approved pharmacotherapies, while others have more limited provision. Patients should enquire with their GP about local services and commissioning arrangements.

For those interested in participating in clinical trials of maridebart cafraglutide, the NIHR 'Be Part of Research' registry (www.bepartofresearch.nihr.ac.uk) and ClinicalTrials.gov maintain registries of ongoing studies. Participation in clinical trials provides access to investigational treatments under close medical supervision, though eligibility criteria are typically strict and not all participants receive the active treatment due to randomisation and placebo controls.

It is important to note that private prescription of unlicensed medicines is not appropriate for maridebart cafraglutide at this stage of development. Patients should be cautious of any providers offering access to investigational obesity treatments outside of legitimate clinical trials, as this raises significant safety and regulatory concerns.

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