hrp0082pl6 | Genetics of Obesity | ESPE2014

Making a Diagnosis in Severe Complex Obesity

Farooqi Sadaf

With the rising prevalence of childhood obesity, there has been an increase in the number of children presenting with severe obesity. Whilst only a relatively small proportion of severely obese children will have the classical features associated with the well-established genetic obesity syndromes such as Prader-Willi syndrome, there is increasing recognition that highly penetrant genetic disorders can frequently present as severe obesity alone without developmental delay, dys...

hrp0089p1-p106 | Fat, Metabolism and Obesity P1 | ESPE2018

Towards a Greater Understanding of the Pathophysiology of Obesity: Hypothalamic Obesity as a Model of Dysregulation of Appetite and Metabolic Homeostasis

Gan Hoong-Wei , Leeson Clare , Aitkenhead Helen , Farooqi Sadaf , Spoudeas Helen , Dattani Mehul

Introduction: Hypothalamic obesity (HyOb) is a rare form of treatment-resistant morbid obesity associated with congenital or acquired hypothalamic damage. Its pathophysiology is incompletely understood, with weight gain being attributed to hyperphagia and hyperinsulinaemia. We sought to compare the physiology of various plasma appetite-regulating hormones in HyOb and ‘simple’ obesity (Ob) to improve our understanding of both forms of obesity and identify novel therap...

hrp0084p2-333 | Fat | ESPE2015

Leptin Replacement Improves Central Ventilation in a Patient with Congenital Leptin Deficiency: First Report in Childhood

Lucaccioni Laura , Davies Philip L , Gibson Neil A , Farooqi Sadaf , Shaikh M Guftar

Background: Congenital leptin deficiency (CLD) is characterized by severe early-onset obesity due to hyperphagia and impaired satiety. The impact of obesity in obstructive sleep apnoea hypopnoea syndrome (OSAHS) was originally reported as mechanical, but recent data suggest that adipokines may influence central ventilation. We highlight that treatment with recombinant human leptin (RHL) in CLD with OSAHS improves ventilation before weight loss.Case prese...

hrp0094p1-31 | Fat, Metabolism and Obesity A | ESPE2021

Efficacy and Safety of Setmelanotide in Individuals With Obesity Due to POMC or LEPR Deficiency: Phase 3 Results From Pivotal and Supplemental Cohorts

Farooqi Sadaf , Miller Jennifer , Ohayon Olga , Yuan Guojun , Scimia Cecilia , Stewart Murray , Yanovski Jack ,

Background: Disruption of the melanocortin-4 receptor pathway by genetic variants in POMC/PCSK1 or LEPR can result in hyperphagia and severe early-onset obesity. In the primary analyses of 2 pivotal Phase 3 trials, the melanocortin-4 receptor agonist setmelanotide was associated with significant reductions in body weight and hunger in patients with obesity due to proopiomelanocortin (POMC) or leptin receptor (LEPR) deficiency. These ...

hrp0094p2-222 | Fat, metabolism and obesity | ESPE2021

Design of a Phase 2, Double-Blind, Placebo-Controlled Trial of Setmelanotide in Patients With Genetic Variants in the Melanocortin-4 Receptor Pathway

Farooqi Sadaf , Wabitsch Martin , Chung Wendy , Ohayon Olga , Scimia Cecilia , Yuan Guojun , Shah Bhavik , Stewart Murray ,

Background: Rare genetic causes of obesity include variants in genes within the melanocortin-4 receptor (MC4R) pathway, a principal regulator of energy balance. Weight and hunger reductions following treatment with the MC4R agonist setmelanotide have been demonstrated in patients with obesity due to variants in multiple genes, including POMC, LEPR, SRC1, and SH2B1. We describe a trial design of setmelanotide in patients with addition...

hrp0094fc2.1 | Fat, Metabolism and Obesity | ESPE2021

Efficacy and Safety Results of a Phase 2 Trial of Setmelanotide in Obesity Due to SH2B1 Variants and 16p11.2 Deletion Syndrome

Argente Jesus , Farooqi Sadaf , Oral Elif , Goldstone Anthony , Ohayon Olga , Scimia Cecilia , Yuan Guojun , Stewart Murray , Chung Wendy ,

Background: Variants in SH2B1 or a 220–kilobase pair distal deletion of chromosome 16p11.2, including SH2B1, are associated with severe, early-onset obesity and hyperphagia. The melanocortin-4 receptor (MC4R) agonist setmelanotide is being investigated in individuals with rare variants in genes in the MC4R pathway.Methods: This ongoing, Phase 2 study (NCT03013543) enrolled individuals aged ≥6...

hrp0084fc8.4 | Obesity - Basic | ESPE2015

Severe Early-Onset Obesity Caused By Bioinactive Leptin due to a N103K Mutation

Wabitsch Martin , Funcke Jan-Bernd , von Schnurbein Julia , Denzer Friederike , Lahr Georgia , Denzer Christian , Moss Anja , Debatin Klaus-Michael , Gierschik Peter , Farooqi Sadaf , Moepps Barbara , Fischer-Posovszky Pamela

Background: Early-onset severe obesity due to leptin deficiency typically results from a defect of leptin production or secretion due to mutations in the leptin gene. Recently we described a new form of leptin deficiency caused by bioinactivity of the hormone and associated with high circulating leptin levels (New England Journal of Medicine 2015 372 48–54).Method: Serum leptin was measured by ELISA. The leptin gene was seq...

hrp0095p1-472 | Fat, Metabolism and Obesity | ESPE2022

Venture: Design of a Phase 3 Multicenter, 1-Year, Open-Label Trial of Setmelanotide in Pediatric Patients Aged 2 to <6 Years With Rare Genetic Diseases of Obesity

Farooqi Sadaf , Mohamed Iqbal Anoop , Fennoy Ilene , M. Kelsey Megan , F. Verge Charles , Cokkinias Casey , Lee Hak-Myung , Navarria Andrea , Argente Jesús

Background: Rare genetic diseases of obesity are often driven by gene variants in the melanocortin-4 receptor (MC4R) pathway. The MC4R agonist setmelanotide demonstrated significant reductions in body weight in patients ≥6 years old with various rare genetic diseases of obesity, including proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency and Bardet-Biedl syndrome (BBS). While these condit...

hrp0094fc2.3 | Fat, Metabolism and Obesity | ESPE2021

A Phase 2 Trial of the Melanocortin-4 Receptor Agonist Setmelanotide in Obesity Due to SRC1 Insufficiency: Body Weight, Body Mass Index Z Score, and Safety Results

Farooqi Sadaf , Argente Jesus , Martos-Moreno Gabriel , Oral Elif , Spiliotis Bessie , Kostopoulou Eirini , Pinhas-Hamiel Orit , Ben-Ami Michal , Ohayon Olga , Scimia Cecilia , Yuan Guojun , Stewart Murray , McCormack Shana ,

Background: Rare genetic diseases of obesity can be caused by genetic variants leading to disrupted activity of the melanocortin-4 receptor pathway (MC4R). Setmelanotide, an MC4R agonist, is being investigated in a basket study of populations with rare variants in different genes in the MC4R pathway who have early-onset, severe obesity and hyperphagia.Methods: This ongoing, Phase 2, open-label study (NCT03013543) enrolle...

hrp0095rfc4.2 | Fat, Metabolism and Obesity | ESPE2022

Effect of Setmelanotide Treatment in Children and Adolescents With Proopiomelanocortin (POMC) Deficiency, Leptin Receptor (LEPR) Deficiency, and Bardet-Biedl Syndrome (BBS)

Argente Jesús , Kühnen Peter , M. Haqq Andrea , Wabitsch Martin , K. Chung Wendy , van den Akker Erica , Á. Martos-Moreno Gabriel , Mohamed Iqbal Anoop , Forsythe Elizabeth , Dubern Béatrice , Malhotra Sonali , Yuan Goujun , Touchot Nicolas , Dollfus Hélène , Farooqi Sadaf , Clément Karine

Background: The melanocortin-4 receptor (MC4R) pathway is a key regulator of energy balance and satiety. Variants in genes upstream of MC4R encoding leptin receptor (LEPR), proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1(PCSK1) and those involved in Bardet-Biedl syndrome (BBS) can impair MC4R pathway signaling. Clinically, these variants are characterized by hyperphagia (Pathologic insatiable hunger) and early-onset, severe obesity. E...