Real-World Effects of MC4R Agonist Therapy in BBS and Severe Genetic Obesity (REAL-MC4)

Real-World Effectiveness, Safety and Patient-reported Outcomes of Setmelanotide in Patients With Bardet-Biedl Syndrome: A Prospective Mono Centric Observational Interventional Study

Bardet-Biedl syndrome (BBS) and other rare disorders associated with impairment of the melanocortin-4 receptor (MC4R) pathway are characterized by severe early-onset obesity, hyperphagia, and substantial morbidity. Setmelanotide, an MC4R agonist, is approved in Europe for selected genetic obesity disorders and reimbursed in Germany for eligible patients. This study aims to evaluate the effectiveness, safety, treatment persistence, metabolic outcomes, and patient-reported outcomes of Setmelanotide under real-world conditions. The registry is designed to allow future inclusion of additional MC4R agonists as they become approved and clinically available. The study will primarily be conducted at University Hospital Essen and will collect longitudinal routine clinical data from pediatric and adult patients receiving MC4R agonist therapy according to approved indications.

Study Overview

• Status: Recruiting
• Conditions: Alstrom Syndrome; Bardet Biedl Syndrome; Bardet Biedl Syndrome (BBS); Bardet-Biedl Syndrome (BBS)
• Intervention / Treatment: Drug: Setmelanotide

Detailed Description

The MC4R signaling pathway is a key regulator of appetite and energy balance. Genetic defects affecting this pathway lead to severe obesity syndromes including Bardet-Biedl syndrome and other rare monogenic obesity disorders. Although pivotal clinical trials demonstrated efficacy of Setmelanotide, evidence from routine clinical care remains limited. This study seeks to characterize treatment outcomes in everyday clinical practice, including changes in body weight, BMI, hyperphagia, metabolic parameters, quality of life, treatment adherence, and adverse events. Patients receiving approved MC4R agonist therapy will be followed prospectively. Data will be collected during routine outpatient visits and include anthropometric, clinical, laboratory, and patient-reported measures. The study infrastructure is intended to serve as a platform for future MC4R agonists approved for severe genetic obesity disorders.

• Study Type: Interventional
• Enrollment (Estimated): 200
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Tom Hühne, Dr. med.; Phone Number: +49 201 723 86211; Email: tom.huehne@uk-essen.de
• Study Contact Backup: Name: Lars Dinkelbach, Dr. med.; Email: lars.dinkelbach@uk-essen.de

Study Locations

• Germany
  • Essen, Germany, 45147
    • Recruiting
    • University Hospital Essen, Deparment of Pediatrics II
    • Contact: Metin Cetiner, PD Dr. med.; Phone Number: +49 201 723 84722; Email: metin.cetiner@uk-essen.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• clinical phenotype corresponding to Bardet-Biedl Syndrome
• genetic testing with notable finding

Exclusion Criteria:

• patients younger than the age approved for treatment with setmelanotide

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MC4R Therapy; Patients receiving approved MC4 receptor agonists according to licensed indications and routine clinical practice.	Drug: Setmelanotide; Administration according to approved product labeling and treating physician discretion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent change in BMI z-score	Relative change in BMI z-Score after initiation of MC4 receptor agonist therapy	Baseline to 12/24/36/48/60/72 months
Impact on lipid profile	Changes in lipid profile measured by cholesterol blood levels	Baseline to 12/24/36/48/60/72 months
Change in Hepatic Fat Attenuation	Hepatic Fat Attenuation will be measured by ultrasound Attenuation imaging across different time points	Baseline to 12/24/36/48/60/72 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Life quality	Patient-reported quality of life using e.g. the "Impact of weight on Quality of life"-questionnaire (IWQOL). The assessment is based on a scale from 0 to 100, with 100 representing the best possible weight-related quality of life.	Baseline to 12/24/36/48/60/72 months
Safety and Tolerability	Incidence of adverse events, serious adverse events and treatment discontinuations and reasons for it	Baseline to 12/24/36/48/60/72 months
Cognitive changes	Neurocognitive impairment is common in Bardet-Biedl Syndrome. Wechsler Intelligence Scale for Children - Fourth Edition (WISC-IV) for children and Wechsler Adult Intelligence Scale (WAIS) for adults are performed to investigate cognition before and after intervention.	Baseline to 12/24/36/48/60/72 months
Functional brain connectivity	Newly diagnosed patients undergo non-invasive functional magnetic resonance imaging (fMRI) both prior to treatment initiation and three months afterward. The scanning protocol will include structural T1-weighted MRI sequences (8 minutes), resting-state fMRI (4 runs of 5.5 minutes each; 22 minutes total), and task-based fMRI to assess responses to high- and low-fat food cues (2 runs of 5.5 minutes each; 11 minutes total). The imaging component will enable the investigation of treatment-related changes in functional brain connectivity associated with setmelanotide.	Baseline to 12/24/36/48/60/72 months
Changes on hypothalamic-pituitary-gonadal axis	Hypothalamic-pituitary-gonadal axis is investigated by longitudinal measurements of testosterone and estradiol levels in blood.	Baseline to 12/24/36/48/60/72 months

Collaborators and Investigators

• Sponsor: Tom Hühne
• Collaborators: Rhythm Pharmaceuticals, Inc.
• Investigators: Principal Investigator: Metin Cetiner, PD Dr. med., Universitätsmedizin Essen

Publications and helpful links

General Publications

• Collet TH, Dubern B, Mokrosinski J, Connors H, Keogh JM, Mendes de Oliveira E, Henning E, Poitou-Bernert C, Oppert JM, Tounian P, Marchelli F, Alili R, Le Beyec J, Pepin D, Lacorte JM, Gottesdiener A, Bounds R, Sharma S, Folster C, Henderson B, O'Rahilly S, Stoner E, Gottesdiener K, Panaro BL, Cone RD, Clement K, Farooqi IS, Van der Ploeg LHT. Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency. Mol Metab. 2017 Oct;6(10):1321-1329. doi: 10.1016/j.molmet.2017.06.015. Epub 2017 Jul 8.
• Kamermans A, Verhoeven T, van Het Hof B, Koning JJ, Borghuis L, Witte M, van Horssen J, de Vries HE, Rijnsburger M. Setmelanotide, a Novel, Selective Melanocortin Receptor-4 Agonist Exerts Anti-inflammatory Actions in Astrocytes and Promotes an Anti-inflammatory Macrophage Phenotype. Front Immunol. 2019 Oct 4;10:2312. doi: 10.3389/fimmu.2019.02312. eCollection 2019.
• Talbi R, Stincic TL, Ferrari K, Ji Hae C, Walec K, Medve E, Gerutshang A, Leon S, McCarthy EA, Ronnekleiv OK, Kelly MJ, Navarro VM. POMC neurons control fertility through differential signaling of MC4R in kisspeptin neurons. Elife. 2025 Jul 17;13:RP100722. doi: 10.7554/eLife.100722.
• Forsythe E, Haws RM, Argente J, Beales P, Martos-Moreno GA, Dollfus H, Chirila C, Gnanasakthy A, Buckley BC, Mallya UG, Clement K, Haqq AM. Quality of life improvements following one year of setmelanotide in children and adult patients with Bardet-Biedl syndrome: phase 3 trial results. Orphanet J Rare Dis. 2023 Jan 16;18(1):12. doi: 10.1186/s13023-022-02602-4.
• Haqq AM, Chung WK, Dollfus H, Haws RM, Martos-Moreno GA, Poitou C, Yanovski JA, Mittleman RS, Yuan G, Forsythe E, Clement K, Argente J. Efficacy and safety of setmelanotide, a melanocortin-4 receptor agonist, in patients with Bardet-Biedl syndrome and Alstrom syndrome: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial with an open-label period. Lancet Diabetes Endocrinol. 2022 Dec;10(12):859-868. doi: 10.1016/S2213-8587(22)00277-7. Epub 2022 Nov 7.
• Sweeney P, Gimenez LE, Hernandez CC, Cone RD. Targeting the central melanocortin system for the treatment of metabolic disorders. Nat Rev Endocrinol. 2023 Sep;19(9):507-519. doi: 10.1038/s41574-023-00855-y. Epub 2023 Jun 26.
• Barnett S, Reilly S, Carr L, Ojo I, Beales PL, Charman T. Behavioural phenotype of Bardet-Biedl syndrome. J Med Genet. 2002 Dec;39(12):e76. doi: 10.1136/jmg.39.12.e76. No abstract available.
• Cetiner M, Finkelberg I, Schiepek F, Pape L, Hirtz R, Buscher AK. Ultrasound evaluation of kidney and liver involvement in Bardet-Biedl syndrome. Orphanet J Rare Dis. 2024 Nov 12;19(1):425. doi: 10.1186/s13023-024-03400-w.
• Dollfus H, Lilien MR, Maffei P, Verloes A, Muller J, Bacci GM, Cetiner M, van den Akker ELT, Grudzinska Pechhacker M, Testa F, Lacombe D, Stokman MF, Simonelli F, Gouronc A, Gavard A, van Haelst MM, Koenig J, Rossignol S, Bergmann C, Zacchia M, Leroy BP, Mosbah H, Van Eerde AM, Mekahli D, Servais A, Poitou C, Valverde D. Bardet-Biedl syndrome improved diagnosis criteria and management: Inter European Reference Networks consensus statement and recommendations. Eur J Hum Genet. 2024 Nov;32(11):1347-1360. doi: 10.1038/s41431-024-01634-7. Epub 2024 Jul 31.
• Huhne T, Polichronidou IM, Finkelberg I, Brensing P, Jaegers J, Dinkelbach L, Kiewert C, Galetzka W, Huessler EM, Scherer T, Bokenkamp A, Gackler A, Pape L, Cetiner M. Impact of the Melanocortin-4 Receptor Agonist Setmelanotide on MASLD and Kidney Function in Bardet-Biedl Syndrome. J Clin Endocrinol Metab. 2026 Feb 20;111(3):721-733. doi: 10.1210/clinem/dgaf483.

Helpful Links

• The CoE is dedicated to researching the connections between endocrinology, genetics, neuroscience and metabolism, in particular their regulation via melanocortin receptor signalling pathways in healthy individuals and in common and rare diseases from the

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2023
• Primary Completion (Estimated): December 31, 2030
• Study Completion (Estimated): December 31, 2030

Study Registration Dates

• First Submitted: June 16, 2026
• First Submitted That Met QC Criteria: June 23, 2026
• First Posted (Actual): June 29, 2026

Study Record Updates

• Last Update Posted (Actual): June 29, 2026
• Last Update Submitted That Met QC Criteria: June 23, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Bardet-Biedl Syndrome; Hyperphagia; Genetic Obesity; Neurocognitive development; Setmelanotide; Melanocortin-4-receptor; Melanocortin pathway
• Additional Relevant MeSH Terms: Ciliopathies; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Genetic Diseases, Inborn; Signs and Symptoms, Digestive; Peripheral Nervous System Diseases; Eye Diseases; Neurodegenerative Diseases; Eye Diseases, Hereditary; Congenital Abnormalities; Abnormalities, Multiple; Heredodegenerative Disorders, Nervous System; Nervous System Malformations; Hypothalamic Diseases; Polyneuropathies; Retinitis Pigmentosa; Hereditary Sensory and Motor Neuropathy; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Hyperphagia; Bardet-Biedl Syndrome; Alstrom Syndrome; setmelanotide
• Other Study ID Numbers: UME-BBS-RWD-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Due to the nature of the study population (pediatric/vulnerable) and consent limitations, sharing of de-identified IPD is not planned at this time. Requests for data access may be considered on a case-by-case basis.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No