👤 Metin Cetiner

The melanocortin-4 receptor agonist setmelanotide compensates for upstream gene defects in the brain leptin-melanocortin pathway and reduces hyperphagia and obesity in selected monogenic obesity forms and Bardet-Biedl syndrome (BBS). We aimed to evaluate the short-term impact of setmelanotide treatment in BBS presenting original real-world data focusing on metabolic dysfunction-associated steatotic liver disease (MASLD) and kidney function. This monocentric, prospective observational cohort study was performed between June and December 2023 and included patients above the age of 6 years with genetically confirmed BBS, obesity, and/or hyperphagia and planned setmelanotide therapy. Ultrasound examination of the liver including shear wave elastography, dispersion and attenuation imaging (ATI), a bioimpedance analysis, and a hyperphagia questionnaire survey were applied in addition to clinical data collection. Twenty-six patients with BBS (mean age 19.2 years, range [6.2; 51.8]; mean body mass index (BMI) z-score 2.95, range [1.32; 4.84]) were included. All were classified with MASLD (54% S3, 23% each S1 and S2). After 6 months of setmelanotide treatment, estimated glomerular filtration rate increased up to 10.1 mL/min/1.73 m² (95% confidence interval (CI) [4.3; 15.9]). The following parameters also improved: BMI z-score -0.5 (95% CI [-0.6; -0.3]); hyperphagia score -12.3 (95% CI [-15.5; -9.0]); total body fat -3.1% (95% CI [-5.7; -0.5]); ATI -0.14 dB/cm/MHZ (95% CI [-0.17; -0.11]). A total of 85% of patients exhibited either resolution of MASLD or stabilization at grade S1. MASLD improvement correlated only with liver size, not BMI reduction. Setmelanotide treatment is associated with improvement of MASLD independent of BMI reduction as well as increased glomerular filtration rate in BBS. Show less

A total of 150 clinicians and researchers representing 19 countries came together in person and online to participate in the highly anticipated 2nd International Meeting on Pathway-Related Obesity: Vision & Evidence (IMPROVE), held on 13-15 December 2023 in Paris, France. Building on the success of the inaugural event in 2022, this gathering served as a pivotal platform for attendees to delve into the latest scientific and clinical developments in hyperphagia and early-onset obesity caused by rare melanocortin-4 receptor (MC4R) pathway disease. The central objective of the meeting was to explore the complexities of MC4R pathway-related diseases and generate opportunities for collaborative dialogue among delegates for the advancement of this field. The event unfolded across three distinct sessions, with a dedicated focus on monogenic MC4R pathway disease, Bardet-Biedl syndrome (BBS) and hypothalamic obesity, together with a discussion on the future of the field. Additionally, the agenda featured three insightful workshops designed to facilitate in-depth discussions. One workshop focused on the genetics of monogenic MC4R pathway diseases, another scrutinised the genetics of BBS and the final workshop examined patient management through the exploration of clinical cases. As we reflect on the wealth of information disseminated and the collaborative spirit that permeated the meeting, it becomes clear that IMPROVE 2023 was not merely an assembly of professionals; it was a forum where the future of research in rare MC4R pathway diseases and patient care took centre stage. Here, we encapsulate the key insights, discussions, and initiatives that emerged from this important meeting. Show less

Bardet-Biedl syndrome (BBS) is a rare, genetically heterogeneous, and highly pleiotropic autosomal recessive ciliopathy. Patients typically present with early loss of vision, hyperphagia, severe obesity, learning difficulties, and renal dysfunction. In patients with BBS, dysfunction of the immotile primary cilia in the hypothalamic melanocortin-4 receptor (MC4R) pathway responsible for controlling energy balance, hunger, and satiety results in severe hyperphagia manifesting in food-seeking behaviors that drive the development of obesity early in childhood. These behaviors have negative impacts on many areas of the lives of patients with BBS and their families/caregivers, including sleep, mood, school/work, and social/family relationships. Additionally, many patients feel stigmatized due to their hyperphagia-associated food-seeking behaviors and the resulting obesity, which exacerbates the impacts of hyperphagia on quality of life. Early identification and management of hyperphagia in patients with BBS is key: mitigating food-seeking and weight gain can improve quality of life and reduce the risk of metabolic and cardiovascular diseases that is increased in patients with BBS. Until recently, the only treatment strategies available were lifestyle and diet modifications. However, targeted treatment with the novel MC4R agonist setmelanotide now offers an effective management option to reduce hyperphagia and weight in patients with BBS, improving overall health and quality of life. Show less