The efficacy and safety of setmelanotide in individuals with Bardet-Biedl syndrome or Alström syndrome: Phase 3 trial design

Haws, Robert; Gordon, Gregory; Han, Joan C.; Yanovski, Jack A.; Gao, Yuan; Stewart, Murray

doi:10.1016/j.conctc.2021.100780

Cited by 35 publications

(35 citation statements)

References 21 publications

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“…Setmelanotide is a selective MC4 receptor agonist licensed for 6 years and older with obesity due to pro-opiomelanocortin deficiency, proprotein subtilisin/kexin type 1 (PCSK1) deficiency, and leptin receptor (LEPR) deficiency confirmed by genetic testing and is currently being trialled in other rare genetic disorders associated with obesity including Bardet-Biedl Syndrome and Alström Syndrome ( 138 , 139 ). Setmelanotide stimulates MC4 receptors in the PVN and LH to activate anorexigenic pathways ( 140 , 141 ).…”

Section: Novel Therapeutic Approaches – Future Therapies For Hypothal...mentioning

confidence: 99%

Treatment of Acquired Hypothalamic Obesity: Now and the Future

Dimitri

2022

Front. Endocrinol.

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The hypothalamus is the centre of neuroendocrine regulation of energy homeostasis and appetite. Maldevelopment of, or damage to, the key hypothalamic nuclei disrupts the coordinated balance between energy intake and expenditure leading, to rapid and excessive weight gain. Hypothalamic obesity is compounded by a disruption of the hypothalamic-pituitary axis, sleep disruption, visual compromise, and neurological and vascular sequalae. Amongst suprasellar tumors, craniopharyngioma is the most common cause of acquired hypothalamic obesity, either directly or following surgical or radiotherapeutic intervention. At present, therapy is limited to strategies to manage obesity but with a modest and variable impact. Current approaches include optimizing pituitary hormone replacement, calorie restriction, increased energy expenditure through physical activity, behavioral interventions, pharmacotherapy and bariatric surgery. Current pharmacotherapeutic approaches include stimulants that increase energy consumption, anti-diabetic agents, hypothalamic–pituitary substitution therapy, octreotide, and methionine aminopeptidase 2 (MetAP2) inhibitors. Some pharmacological studies of hypothalamic obesity report weight loss or stabilization but reported intervention periods are short, and others report no effect. The impact of bariatric surgery on weight loss in hypothalamic obesity again is variable. Novel or combined approaches to manage hypothalamic obesity are thus required to achieve credible and sustained weight loss. Identifying etiological factors contributing hypothalamic obesity may lead to multi-faceted interventions targeting hyperphagia, insulin resistance, decreased energy expenditure, sleep disturbance, hypopituitarism and psychosocial morbidity. Placebo-controlled trials using current single, or combination therapies are required to determine the impact of therapeutic agents. A well-defined approach to defining the location of hypothalamic damage may support the use of future targeted therapies. Intranasal oxytocin is currently being investigated as an anorexogenic agent. Novel agents including those targeting pro-opimelanocortin-C and AgRP/NPY expressing neurons and the MC4 receptor may result in better outcomes. This article discusses the current challenges in the management of hypothalamic obesity in children and young people and future therapeutic approaches to increasing weight loss and quality of life in these patients.

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Section: Novel Therapeutic Approaches – Future Therapies For Hypothal...mentioning

confidence: 99%

Treatment of Acquired Hypothalamic Obesity: Now and the Future

Dimitri

2022

Front. Endocrinol.

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“…8,15,16) Treatment of obesity in BBS using MC4R agonist was evaluated and showed beneficial effect in clinical trials. 3,17,18)…”

Section: Bardet-biedle Syndromementioning

confidence: 99%

Genetic obesity: an update with emerging therapeutic approaches

Sohn

2022

Ann Pediatr Endocrinol Metab

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Based on the genetic contribution, childhood obesity can be classified into 3 groups: common polygenic obesity, syndromic obesity, and monogenic obesity. More genetic causes of obesity are being identified along with the advances in the genetic testing. Genetic obesities including syndromic and monogenic obesity should be suspected and evaluated in children with early-onset morbid obesity and hyperphagia under 5 years of age. Patients with syndromic obesity have early-onset severe obesity associated specific genetic syndromes including Prader-Willi syndrome, Bardet-Biedle syndrome, and Alstrom syndrome. Syndromic obesity is often accompanied with neurodevelopmental delay or dysmorphic features. Nonsyndromic monogenic obesity is caused by variants in single gene which are usually involved in the regulation of hunger and satiety associated with the hypothalamic leptin-melanocortin pathway in central nervous system. Unlike syndromic obesity, patients with monogenic obesity usually show normal neurodevelopment. They would be presented with hyperphagia and early-onset severe obesity with additional clinical symptoms including short stature, red hair, adrenal insufficiency, hypothyroidism, hypogonadism, pituitary insufficiencies, diabetes insipidus, increased predisposition to infection or intractable recurrent diarrhea. Identifying patients with genetic obesity is critical as new innovative therapies including melanocortin 4 receptor agonist have become available. Early genetic evaluation enables to identify treatable obesity and provide timely intervention which may eventually achieve favorable outcome by establishing personalized management.

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“…37 There are promising results in studies of subcutaneous injection treatment with setmelanotide, a melanocortin 4 receptor agonist, studied now in Phase 3 clinical trials. 39 The clinical group evaluated by Haws RM et al included individuals aged >6 years old, with a diagnosis of BBS or Alström syndrome, treated with randomized, double-blind, placebo-controlled therapy. They selected individuals with body mass index ≥30 kg/m 2 (aged ≥16 years old) or weight >97th percentile (aged 6-15 years old).…”

Section: Obesitymentioning

confidence: 99%

“…These results include, in BBS patients, weight loss and feelings of early satiety. 39 Hypogonadotropic Hypogonadism and/or Genitourinary Anomalies…”

Section: Obesitymentioning

confidence: 99%

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Monitoring and Management of Bardet-Biedl Syndrome: What the Multi-Disciplinary Team Can Do

Caba¹,

Florea²,

Braha³

et al. 2022

JMDH

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Bardet -Biedl syndrome is a rare autosomal recessive multisystem non-motile ciliopathy. It has heterogeneous clinical manifestations. It is caused by mutations in 26 genes encoding BBSome proteins, chaperonines, and IFT complex. The main clinical features are: retinal cone-rod dystrophy, central obesity, postaxial polydactyly, cognitive impairment, hypogonadism and genitourinary anomalies, and kidney disease. The onset of clinical manifestations is variable which makes the diagnosis difficult in some patients. Because of the multiple system involvement, a multidisciplinary approach is necessary. The purpose of this review is to provide monitoring and management directions for a better approach to these patients.

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The efficacy and safety of setmelanotide in individuals with Bardet-Biedl syndrome or Alström syndrome: Phase 3 trial design

Cited by 35 publications

References 21 publications

Treatment of Acquired Hypothalamic Obesity: Now and the Future

Treatment of Acquired Hypothalamic Obesity: Now and the Future

Genetic obesity: an update with emerging therapeutic approaches

Monitoring and Management of Bardet-Biedl Syndrome: What the Multi-Disciplinary Team Can Do

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