RARE DISEASE
Obesity due to pro-opiomelanocortin deficiency
Obesity due to pro-opiomelanocortin deficiency
Obesity due to pro-opiomelanocortin deficiency
Synonyms: POMC deficiency
Synonyms: POMC deficiency
Synonyms: POMC deficiency
Drug discovery
3
drugs
With orphan designations
Overview
Obesity due to pro-opiomelanocortin (POMC) deficiency is a rare autosomal recessive disorder caused by biallelic POMC mutations, disrupting melanocortin signaling. It presents with severe hyperphagia, early-onset obesity, adrenal insufficiency, and hypopigmentation (red hair, pale skin). Neonates may experience hypoglycemia, seizures, and cholestasis [1][2][15]. Management focuses on glucocorticoid replacement and MC4R agonist therapy (e.g., setmelanotide), which targets hyperphagia and obesity [3][5][7].
Burden
Therapies
Categories: rare endocrine diseases, rare genetic diseases
Research Papers
625 drug discovery papers about Obesity due to pro-opiomelanocortin deficiency, with 2 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
625 drug discovery papers about Obesity due to pro-opiomelanocortin deficiency, with 2 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-04-21 | A systematic literature review of economic evaluations of setmelanotide.
PURPOSE: This systematic literature review (SLR) aimed to assess the economic value of setmelanotide, a selective melanocortin-4 receptor agonist, in the treatment of rare genetic diseases of obesity (RGDOs), specifically Bardet-Biedl syndrome (BBS), pro-opiomelanocortin (POMC) deficiency, and leptin receptor (LEPR) deficiency. METHODS: The SLR was conducted according to PRISMA guidelines and registered on PROSPERO. Systematic searches were performed in Embase, MEDLINE/PubMed, and Global Health, supplemented by manual searches and reference screening. Inclusion criteria included full economic evaluations (cost-effectiveness and cost-utility analyses) published in English since 2019. Data extraction and quality assessment followed established checklists (BMJ, CHEERS 2022), with findings synthesised descriptively due to heterogeneity in study designs and settings. RESULTS: Four studies (one CEA, three CUAs) met inclusion criteria, all employing model-based frameworks from a healthcare payer perspective with a lifetime horizon. Incremental cost-effectiveness ratios (ICERs) varied: NICE appraisals in the UK suggested potentially favorable or even negative ICERs, while the Canadian CADTH review reported ICERs exceeding CAD $2 million/QALY, far above conventional willingness-to-pay thresholds. Key drivers included drug acquisition cost, severity of hyperphagia, and caregiver burden. All studies noted significant uncertainty due to limited long-term data and small patient populations. CONCLUSIONS: While setmelanotide demonstrates clinical benefit in RGDOs, its high cost poses substantial challenges to conventional pharmacoeconomic evaluations. Adoption may require significant price reductions or alternative value assessment frameworks, particularly for rare diseases. Further research is needed to address long-term effectiveness and ethical considerations in economic evaluations.
2026-04-16 | POMC neuron METTL14/m6A/YTHDC1/YTHDF2 pathways safeguard energy balance, body weight, and metabolism.
METTL14 mediates N6-methyladenosine (m6A) RNA modification, while YTHDC1 and YTHDF2 specifically bind m6A-methylated RNA to regulate RNA fate. POMC neurons constitute the core of the central melanocortin circuit, and POMC deficiency causes obesity in both mice and humans. However, how m6A-based epitranscriptomics regulates melanocortin circuit function remains unclear. Here, we generated and characterized POMC neuron-specific knockout mice lacking Mettl14 (Mettl14ΔPOMC), Ythdc1 (Ythdc1ΔPOMC), or Ythdf2 (Ythdf2 ΔPOMC). Mettl14ΔPOMC and Ythdc1ΔPOMC mice develop hyperphagia, obesity, glucose intolerance, insulin resistance, and hepatic steatosis in both sexes under standard chow conditions, accompanied by POMC downregulation. Conversely, POMC neuron-specific overexpression of METTL14 or YTHDC1 protects against diet-induced obesity. In contrast, Ythdf2 ΔPOMC mice are resistant to obesity, revealing an m6A-dependent balance between YTHDC1 and YTHDF2. Mechanistically, the METTL14/YTHDC1 pathway is indispensable for embryonic POMC neurogenesis, while in adults YTHDC1 maintains melanocortin circuit integrity/function. METTL14 and YTHDC1 directly target POMC and ISL1 transcripts to regulate protein expression. POMC neuron-specific restoration of POMC reverses obesity and metabolic phenotypes in Mettl14ΔPOMC and Ythdc1ΔPOMC mice, defining an anti-obesity METTL14/m6A/YTHDC1/POMC axis. These findings identify METTL14 as the m6A writer for POMC/ISL1 and YTHDC1 and YTHDF2 as their readers, uncovering a critical role of m6A epitranscriptomic regulation in melanocortin circuit development and maintenance.
2026-03-31 | TonEBP as a key regulator of hypothalamic leptin signaling and resistance
Tonicity-responsive enhancer binding protein (TonEBP) is a transcription factor implicated in cellular stress and inflammation. Here, we explore the role of TonEBP as a key regulator of leptin signaling and resistance. Using TonEBP haploinsufficient [TonEBP (+/-)] mice, we demonstrated that TonEBP negatively regulates leptin sensitivity by upregulating suppressor of cytokine signaling 3 (SOCS3). TonEBP (+/-) mice exhibited heightened leptin-induced anorexia, increased energy expenditure, and elevated STAT3 phosphorylation in proopiomelanocortin (POMC) neurons compared to wild-type [TonEBP (+/+)] controls. Additionally, TonEBP (+/-) mice were protected from high-fat diet-induced obesity and retained leptin sensitivity during chronic energy surplus conditions. Mechanistically, TonEBP deficiency suppressed SOCS3 expression through decreased NF-κB-mediated transcriptional activation, thereby suppressing the negative feedback signal on leptin signaling. Furthermore, elevated hypothalamic TonEBP expression during high-fat diet feeding and leptin treatment implicates its role in regulating leptin sensitivity. Taken together, these findings identify a novel role for TonEBP as a molecular mediator of hypothalamic leptin signaling.
2026-04-21 | A systematic literature review of economic evaluations of setmelanotide.
PURPOSE: This systematic literature review (SLR) aimed to assess the economic value of setmelanotide, a selective melanocortin-4 receptor agonist, in the treatment of rare genetic diseases of obesity (RGDOs), specifically Bardet-Biedl syndrome (BBS), pro-opiomelanocortin (POMC) deficiency, and leptin receptor (LEPR) deficiency. METHODS: The SLR was conducted according to PRISMA guidelines and registered on PROSPERO. Systematic searches were performed in Embase, MEDLINE/PubMed, and Global Health, supplemented by manual searches and reference screening. Inclusion criteria included full economic evaluations (cost-effectiveness and cost-utility analyses) published in English since 2019. Data extraction and quality assessment followed established checklists (BMJ, CHEERS 2022), with findings synthesised descriptively due to heterogeneity in study designs and settings. RESULTS: Four studies (one CEA, three CUAs) met inclusion criteria, all employing model-based frameworks from a healthcare payer perspective with a lifetime horizon. Incremental cost-effectiveness ratios (ICERs) varied: NICE appraisals in the UK suggested potentially favorable or even negative ICERs, while the Canadian CADTH review reported ICERs exceeding CAD $2 million/QALY, far above conventional willingness-to-pay thresholds. Key drivers included drug acquisition cost, severity of hyperphagia, and caregiver burden. All studies noted significant uncertainty due to limited long-term data and small patient populations. CONCLUSIONS: While setmelanotide demonstrates clinical benefit in RGDOs, its high cost poses substantial challenges to conventional pharmacoeconomic evaluations. Adoption may require significant price reductions or alternative value assessment frameworks, particularly for rare diseases. Further research is needed to address long-term effectiveness and ethical considerations in economic evaluations.
2026-04-16 | POMC neuron METTL14/m6A/YTHDC1/YTHDF2 pathways safeguard energy balance, body weight, and metabolism.
METTL14 mediates N6-methyladenosine (m6A) RNA modification, while YTHDC1 and YTHDF2 specifically bind m6A-methylated RNA to regulate RNA fate. POMC neurons constitute the core of the central melanocortin circuit, and POMC deficiency causes obesity in both mice and humans. However, how m6A-based epitranscriptomics regulates melanocortin circuit function remains unclear. Here, we generated and characterized POMC neuron-specific knockout mice lacking Mettl14 (Mettl14ΔPOMC), Ythdc1 (Ythdc1ΔPOMC), or Ythdf2 (Ythdf2 ΔPOMC). Mettl14ΔPOMC and Ythdc1ΔPOMC mice develop hyperphagia, obesity, glucose intolerance, insulin resistance, and hepatic steatosis in both sexes under standard chow conditions, accompanied by POMC downregulation. Conversely, POMC neuron-specific overexpression of METTL14 or YTHDC1 protects against diet-induced obesity. In contrast, Ythdf2 ΔPOMC mice are resistant to obesity, revealing an m6A-dependent balance between YTHDC1 and YTHDF2. Mechanistically, the METTL14/YTHDC1 pathway is indispensable for embryonic POMC neurogenesis, while in adults YTHDC1 maintains melanocortin circuit integrity/function. METTL14 and YTHDC1 directly target POMC and ISL1 transcripts to regulate protein expression. POMC neuron-specific restoration of POMC reverses obesity and metabolic phenotypes in Mettl14ΔPOMC and Ythdc1ΔPOMC mice, defining an anti-obesity METTL14/m6A/YTHDC1/POMC axis. These findings identify METTL14 as the m6A writer for POMC/ISL1 and YTHDC1 and YTHDF2 as their readers, uncovering a critical role of m6A epitranscriptomic regulation in melanocortin circuit development and maintenance.
2026-03-31 | TonEBP as a key regulator of hypothalamic leptin signaling and resistance
Tonicity-responsive enhancer binding protein (TonEBP) is a transcription factor implicated in cellular stress and inflammation. Here, we explore the role of TonEBP as a key regulator of leptin signaling and resistance. Using TonEBP haploinsufficient [TonEBP (+/-)] mice, we demonstrated that TonEBP negatively regulates leptin sensitivity by upregulating suppressor of cytokine signaling 3 (SOCS3). TonEBP (+/-) mice exhibited heightened leptin-induced anorexia, increased energy expenditure, and elevated STAT3 phosphorylation in proopiomelanocortin (POMC) neurons compared to wild-type [TonEBP (+/+)] controls. Additionally, TonEBP (+/-) mice were protected from high-fat diet-induced obesity and retained leptin sensitivity during chronic energy surplus conditions. Mechanistically, TonEBP deficiency suppressed SOCS3 expression through decreased NF-κB-mediated transcriptional activation, thereby suppressing the negative feedback signal on leptin signaling. Furthermore, elevated hypothalamic TonEBP expression during high-fat diet feeding and leptin treatment implicates its role in regulating leptin sensitivity. Taken together, these findings identify a novel role for TonEBP as a molecular mediator of hypothalamic leptin signaling.
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Drug Discovery Landscape
3 orphan drug designations for Obesity due to pro-opiomelanocortin deficiency, including 2 approved therapies.
3 orphan drug designations for Obesity due to pro-opiomelanocortin deficiency, including 2 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
oral melanocortin 4 receptor agonist | small molecules | FDA | 2022-06-06 | — | Rhythm Pharmaceuticals, Inc. |
Setmelanotide [Imcivree] | peptides | EMA | 2016-07-14 | 2021-07-19 | Rhythm Pharmaceuticals Netherlands B.V. |
setmelanotide [Imcivree] | peptides | FDA | 2016-04-04 | 2020-11-25 | Rhythm Pharmaceuticals, Inc. |
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