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| Name | Class |
|---|---|
| Rhythm Pharmaceuticals, Inc. | INDUSTRY |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| MC4R Therapy | Experimental | Patients receiving approved MC4 receptor agonists according to licensed indications and routine clinical practice. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Setmelanotide | Drug | Administration according to approved product labeling and treating physician discretion |
|
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Tom Hühne, Dr. med. | Contact | +49 201 723 86211 | tom.huehne@uk-essen.de | |
| Lars Dinkelbach, Dr. med. | Contact | lars.dinkelbach@uk-essen.de |
| Name | Affiliation | Role |
|---|---|---|
| Metin Cetiner, PD Dr. med. | Universitätsmedizin Essen | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University Hospital Essen, Deparment of Pediatrics II | Recruiting | Essen | 45147 | Germany |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 29031731 | Background | 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. | |
| 31636637 |
| Label | URL |
|---|---|
| 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 | View source |
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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.
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| ID | Term |
|---|---|
| D020788 | Bardet-Biedl Syndrome |
| D056769 | Alstrom Syndrome |
| D006963 | Hyperphagia |
| ID | Term |
|---|---|
| D007027 | Hypothalamic Diseases |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| C579663 | setmelanotide |
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Prospective real-world observational interventional cohort of patients receiving approved MC4 receptor agonist therapy in routine clinical care.
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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 |
| Background |
| 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. |
| 40674128 | Background | 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. |
| 36647077 | Background | 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. |
| 36356613 | Background | 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. |
| 37365323 | Background | 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. |
| 12471214 | Background | 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. |
| 39533427 | Background | 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. |
| 39085583 | Background | 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. |
| 40903014 | Result | 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. |
| D012174 | Retinitis Pigmentosa |
| D015785 | Eye Diseases, Hereditary |
| D005128 | Eye Diseases |
| D000072661 | Ciliopathies |
| D000015 | Abnormalities, Multiple |
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D030342 | Genetic Diseases, Inborn |
| D015417 | Hereditary Sensory and Motor Neuropathy |
| D009421 | Nervous System Malformations |
| D020271 | Heredodegenerative Disorders, Nervous System |
| D019636 | Neurodegenerative Diseases |
| D011115 | Polyneuropathies |
| D010523 | Peripheral Nervous System Diseases |
| D009468 | Neuromuscular Diseases |
| D012817 | Signs and Symptoms, Digestive |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |