Rhythm Pharmaceuticals announced today that Japan's Ministry of Health, Labour and Welfare (MHLW) has granted orphan drug designation to setmelanotide for the treatment of acquired hypothalamic obesity, marking a significant milestone in addressing this rare neuroendocrine disease.
Setmelanotide, a melanocortin-4 receptor (MC4R) agonist, is designed to treat hyperphagia and obesity by targeting the underlying biological mechanisms of these conditions. The company is currently evaluating the drug in a global Phase 3 clinical trial for patients with acquired hypothalamic obesity, with topline data expected in the second quarter of 2025.
"Orphan drug designation points to the need for therapeutic options for people living with acquired hypothalamic obesity," said Yann Mazabraud, Executive Vice President, Head of International at Rhythm Pharmaceuticals. "With this designation now in place in Japan, as well as in Europe, we believe we are well positioned to execute on our global strategy to bring patients with hypothalamic obesity the first-ever treatment targeting the underlying biology of this disease, pending success of our Phase 3 trial and subsequent regulatory filings."
Understanding Acquired Hypothalamic Obesity
Acquired hypothalamic obesity is characterized by accelerated and sustained weight gain resulting from injury to the hypothalamus, a region of the brain that regulates metabolism and appetite. The condition is often accompanied by hyperphagia—pathological, insatiable hunger with impaired satiety and abnormal food-seeking behaviors—and/or decreased energy expenditure.
The most common cause of hypothalamic obesity is damage from the growth or surgical removal of brain tumors such as craniopharyngioma or astrocytoma. Other causes include traumatic brain injury, stroke, or inflammation due to infection.
Professor Arima, MD, PhD, from the Department of Endocrinology and Diabetes at Nagoya University Graduate School of Medicine, emphasized the significant unmet medical need in Japan: "There is a significant unmet medical need in Japan for a safe and effective precision medicine for patients living with acquired hypothalamic obesity. Setmelanotide could provide new hope to these patients and their families."
Orphan Drug Designation and Market Potential
In Japan, orphan drug designation is granted to treatments for diseases affecting fewer than 50,000 patients where there is a high medical need. Rhythm Pharmaceuticals estimates that approximately 5,000 to 8,000 people in Japan are living with acquired hypothalamic obesity. The company also estimates 5,000 to 10,000 patients in the United States and 3,500 to 10,000 in the European Union.
This designation in Japan follows a similar designation in Europe, strengthening Rhythm's global strategy for setmelanotide.
Current Approvals and Development Pipeline
Setmelanotide, marketed as IMCIVREE®, is already approved by regulatory authorities in multiple regions:
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In the United States, it is approved to reduce excess body weight and maintain weight reduction in adult and pediatric patients 2 years and older with syndromic or monogenic obesity due to Bardet-Biedl syndrome (BBS) or genetically confirmed pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1) deficiency, or leptin receptor (LEPR) deficiency.
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The European Commission and the UK's Medicines & Healthcare Products Regulatory Agency have authorized setmelanotide for similar indications in adults and children 2 years of age and above.
Beyond hypothalamic obesity, Rhythm is advancing a broad clinical development program for setmelanotide in other rare diseases, as well as investigating MC4R agonists LB54640 and RM-718. The company is also developing a preclinical suite of small molecules for the treatment of congenital hyperinsulinism.
Safety Profile
The most common adverse reactions reported with setmelanotide (incidence ≥20%) include skin hyperpigmentation, injection site reactions, nausea, headache, diarrhea, abdominal pain, vomiting, depression, and spontaneous penile erection.
Healthcare providers should be aware of warnings and precautions including disturbance in sexual arousal, depression and suicidal ideation, hypersensitivity reactions, and skin hyperpigmentation. The drug is not recommended during breastfeeding and should be discontinued when pregnancy is recognized unless benefits outweigh potential risks.
Looking Forward
The orphan drug designation in Japan represents an important step in Rhythm's efforts to address the significant unmet needs of patients with hypothalamic obesity globally. If the Phase 3 trial is successful, setmelanotide could become the first approved treatment specifically targeting the underlying biology of acquired hypothalamic obesity, potentially transforming care for patients with this challenging condition.
As the company awaits topline data from its Phase 3 trial in the second quarter of 2025, this regulatory milestone strengthens its position in the global rare disease landscape and highlights the growing recognition of hypothalamic obesity as a serious medical condition requiring targeted therapeutic interventions.
