Our Focus

“As we advance our understanding of the underlying biology of the MC4R pathway, our clinical development programs are designed to evaluate and bring a potential new treatment option to individuals living with severe obesity and hyperphagia.”

– Murray Stewart, MD, Chief Medical Officer

Rare genetic diseases of obesity may be caused by an impaired melanocortin-4 receptor (MC4R) pathway resulting from genetic variants. Setmelanotide, Rhythm’s investigational drug which is an MC4R agonist, has the potential to restore the function of an impaired MC4R pathway, and in doing so, help to reduce hunger and body weight in individuals living with these diseases. Rhythm is currently focused on investigating the efficacy and safety of setmelanotide in the treatment of several rare genetic diseases.

Clinically, these diseases share the hallmark characteristics of early-onset severe obesity and insatiable hunger (hyperphagia).

Setmelanotide Phase 3 Pivotal Studies

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Proopiomelanocortin (POMC) deficiency obesity

Caused by biallelic variants in either the POMC gene, the source of melancyte-stimulating hormone (MSH), or Proprotein convertase Subtilisin/Kexin Type 1 (PCSK1) gene, which is required for producing MSH from POMC, leading to an absence or decrease in MSH. POMC deficiency is characterized by hyperphagia, rapid weight gain leading to severe obesity, often in early infancy, with individuals demonstrating remarkable weight increases.

~100 – 500 U.S. individuals

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Leptin receptor (LEPR) deficiency obesity

Caused by biallelic variants in the LEPR gene, which encodes for the leptin receptor protein that leptin binds to, leading to insufficient activation of POMC-producing neurons. Individuals with this disorder exhibit hyperphagia and severe obesity from early childhood. LEPR deficiency is also associated with hypogonadism and reduced immune function.

~500 – 2,000 U.S. individuals

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Bardet-Biedl syndrome (BBS)

Caused by variants in the BBS genes, BBS is a rare genetic disorder of obesity associated with impaired cilia function. Cilia dysfunction in the hypothalamus can lead to MC4R pathway dysfunction.

There are more than 20 genes associated with BBS. BBS is characterized by obesity and hyperphagia as well as vision loss, polydactyly, kidney dysfunction and other clinical symptoms. For many people living with BBS, hyperphagia and obesity may often be challenging to manage.

~1,500 – 2,500 U.S. individuals

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Alström syndrome

Caused by variants in the ALMS1 gene, Alström syndrome is a rare genetic disorder of obesity associated with impaired cilia function. Cilia dysfunction in the hypothalamus can lead to MC4R pathway dysfunction.

Alström syndrome can lead to childhood obesity and hyperphagia as well as progressive vision loss, hearing loss, cardiomyopathy, and other clinical symptoms.

~500 – 1,000 worldwide individuals

Setmelanotide Phase 2 Basket Study

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POMC or LEPR heterozygous deficiency obesity (HETs)

Caused by high-impact heterozygous variants in one of the POMC, PCSK1 or LEPR genes, that may lead to decreased production of MSH and predisposition to obesity.

>20,000 U.S. individuals

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SRC1 deficiency obesity

Caused by heterozygous variants in the SRC1 gene, a transcriptional coactivator protein, leading to decreased POMC expression in POMC-producing neurons.

>23,000 U.S. individuals

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SH2B1 deficiency obesity

Caused by heterozygous variants in the SH2B1 gene, which codes for the adaptor protein, leading to decreased LEPR activation. Deficiency in SH2B1 can arise through a variant in the SH2B1 gene or through chromosomal deletions (chromosome 16) that encompass the SH2B1 gene. In both cases, there is a dysfunction/loss of only one copy of the SH2B1 gene.

>24,000 U.S. individuals

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MC4R deficiency obesity

Caused by heterozygous variants in the MC4R gene, which encodes for the MC4R receptor for MSH, leading to insufficient activation of the MC4R pathway. Based on a comprehensive ongoing biochemical screening study, there may be a defined subset of individuals who carry MC4R loss of function variants that may be rescued by an MC4R agonist.

~10,000** U.S. individuals

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Smith-Magenis syndrome

Caused by heterozygous variants in the RAI1 gene, encoding for transcription factor that affects expression of several MC4R pathway genes. Deficiency in RAI1 can arise through a variant in the RAI1 gene or through chromosomal deletions (chromosome 17) that encompass the RAI1 gene. Hyperphagia and obesity associated with Smith-Magenis syndrome may be caused by an overall decrease in the activation of the MC4R pathway.

~2,400 U.S. individuals

* Calculations regarding non-syndromic disorder assume a U.S. population of 327 million, of which 1.7% have early-onset, severe obesity (Hales et al in JAMA – April 2018: Trends Obesity and Severe Obesity Prevalence in US Youth and Adults by Sex and Age, 2007-2008 to 2015-2016);

**Estimated prevalence of U.S. individuals with rescuable variants of the MC4R.

Rhythm’s Uncovering Rare Obesity® Program is the only no-cost, comprehensive genetic testing program for rare genetic diseases of obesity.
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For definitions to select clinical terms within this site, please visit glossary For more information on Rhythm’s publications and presentations, please visit publications