DRUG
Setmelanotide
Administration according to approved product labeling and treating physician discretion
Real-World Effects of MC4R Agonist Therapy in BBS and Severe Genetic Obesity
Status
Recruiting
Phase
Phase 4
Enrollment
200
Locations
1
Results
Not posted
Publications
10
Study summary
What the protocol is testing.
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.
Full 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.
Interventions
Treatment arms and agents.
Timeline
From registration to results.
First posted
Jun 29, 2026
Study start
Jan 1, 2023
Primary completion
Dec 31, 2030
Study completion
Dec 31, 2030
Results posted
Not reported
Registry updated
Jun 29, 2026
Outcomes
What the study measures.
Primary outcomes
Percent change in BMI z-score
Time frame · Baseline to 12/24/36/48/60/72 months
Relative change in BMI z-Score after initiation of MC4 receptor agonist therapy
Impact on lipid profile
Time frame · Baseline to 12/24/36/48/60/72 months
Changes in lipid profile measured by cholesterol blood levels
Change in Hepatic Fat Attenuation
Time frame · Baseline to 12/24/36/48/60/72 months
Hepatic Fat Attenuation will be measured by ultrasound Attenuation imaging across different time points
Secondary outcomes
Life quality
Time frame · Baseline to 12/24/36/48/60/72 months
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.
Safety and Tolerability
Time frame · Baseline to 12/24/36/48/60/72 months
Incidence of adverse events, serious adverse events and treatment discontinuations and reasons for it
Cognitive changes
Time frame · Baseline to 12/24/36/48/60/72 months
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.
Functional brain connectivity
Time frame · Baseline to 12/24/36/48/60/72 months
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.
Changes on hypothalamic-pituitary-gonadal axis
Time frame · Baseline to 12/24/36/48/60/72 months
Hypothalamic-pituitary-gonadal axis is investigated by longitudinal measurements of testosterone and estradiol levels in blood.
Eligibility
Who can take part.
- Minimum age
- Not reported
- Maximum age
- Not reported
- Sex
- ALL
- Healthy volunteers
- No
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 locations
1 registered sites.
Germany. Showing up to 24 locations stored in the fast local snapshot.
University Hospital Essen, Deparment of Pediatrics II
Essen, Germany
Publications
Results and literature.
PMID 29031731 ↗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.PMID 31636637 ↗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.PMID 40674128 ↗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.PMID 36647077 ↗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.PMID 36356613 ↗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.PMID 37365323 ↗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.PMID 12471214 ↗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.PMID 39533427 ↗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.PMID 39085583 ↗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.PMID 40903014 ↗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.
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