Setmelanotide
- Generic Name
- Setmelanotide
- Brand Names
- Imcivree
- Drug Type
- Small Molecule
- Chemical Formula
- C49H68N18O9S2
- CAS Number
- 920014-72-8
- Unique Ingredient Identifier
- N7T15V1FUY
- Background
Setmelanotide is the first available treatment for patients with pro-opiomelanocortin, proprotein subilisin/kexin type 1, or leptin deficiencies. It is an agonist of the melanocortin 4 receptor. Earlier attempts at agonizing MC4R (such as LY2112688) lead to successful weight loss, but also an increase in blood pressure and heart rate. Other earlier treatments for these patients included gastric bypass surgery. Patients taking setmelanotide experienced an average weight loss of 0.6 kg/week.
Imcivree was granted EMA orphan designation on November 19, 2018 and FDA approval on November 25, 2020. On May 4, 2023, it was approved by Health Canada.
- Indication
Setmelanotide is indicated for chronic weight management in patients 6 years and older with obesity due to pro-opiomelanocortin (POMC) deficiency, proprotein subtilisin/kexin type 1 (PCSK1) deficiency, or leptin receptor (LEPR) deficiency as determined by an approved test demonstrating variants in POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance. These conditions affect the MC4R signalling pathway.
Setmelanotide is also indicated for chronic weight management in patients 6 years and older with obesity due to Bardet-Biedl syndrome.
The drug is not reported to be effective in patients with POMC, PCSK1, or LEPR variants classified as benign or likely benign, as well as other types of obesity not listed above.
- Associated Conditions
- Leptin Receptor Deficiency Obesity, Obesity, Pro-opiomelanocortin (POMC) Deficiency Obesity, Proprotein convertase subtilisin/kexin type 1 (PCSK1) deficiency obesity
- Associated Therapies
- Chronic Weight Management therapy
CDMO Market Report: Key Regulatory Approvals and Clinical Advances in March-April 2025
• Multiple CDMOs secured significant contract manufacturing opportunities as regulatory bodies approved new indications for established drugs, particularly in oncology and rare diseases.
• AstraZeneca's portfolio saw substantial growth with expanded approvals for Imfinzi, Tagrisso, and Lynparza, strengthening partnerships with contract manufacturers including Lonza, Dottikon, and Samsung Biologics.
• Contract manufacturers supporting treatments for autoimmune conditions showed strong performance, with Argenx's Vyvgart Hytrulo receiving expanded indications for myasthenia gravis and CIDP.
Rhythm Pharmaceuticals' Imcivree Shows Significant Weight Loss in Phase III Hypothalamic Obesity Trial
• Rhythm Pharmaceuticals' Imcivree (setmelanotide) demonstrated a 19.8% placebo-adjusted reduction in BMI over 52 weeks in patients with acquired hypothalamic obesity, a rare condition caused by hypothalamic damage.
• The TRANSCEND Phase III trial met its primary endpoint with 83% of treated patients achieving at least 5% BMI reduction, while placebo patients experienced a 3.3% BMI increase, supporting potential regulatory filings in Q3 2025.
• If approved for hypothalamic obesity, analysts project Imcivree could exceed $1 billion in annual sales by 2028, significantly expanding its current indications for certain genetic obesity disorders.
Rhythm's Imcivree Shows Significant Weight Loss in Patients with Hypothalamic Obesity
• Rhythm Pharmaceuticals' setmelanotide (Imcivree) demonstrated a 16.5% reduction in body weight compared to a 3.3% gain with placebo in patients with hypothalamic obesity over 52 weeks of treatment.
• The Phase 3 TRANSCEND trial results position Imcivree to potentially become the first approved therapy for obesity caused by brain injury, with regulatory submissions planned for Q3 2025.
• Imcivree works by targeting the melanocortin-4 receptor pathway, differentiating it from GLP-1 obesity drugs like Wegovy and Zepbound, and expanding Rhythm's presence in specialized obesity treatment markets.
GSK Expands Neurodegenerative Disease Portfolio with $2.5B+ ABL Bio Partnership
• GSK has committed to a potential $2.5 billion partnership with South Korea's ABL Bio, providing an upfront payment of £38.5 million to develop novel treatments for neurodegenerative diseases.
• The collaboration centers on ABL Bio's proprietary Grabody-B platform, which utilizes bispecific antibodies targeting insulin-like growth factor 1 receptors to facilitate the transport of therapeutic molecules across the blood-brain barrier.
• This agreement represents GSK's continued strategic expansion into neuroscience, following its recent $35 million partnership with Muna Therapeutics focused on Alzheimer's disease targets.
Setmelanotide Receives Orphan Drug Designation in Japan for Hypothalamic Obesity Treatment
• Rhythm Pharmaceuticals' setmelanotide has received orphan drug designation from Japan's Ministry of Health for the treatment of acquired hypothalamic obesity, a rare condition affecting an estimated 5,000-8,000 patients in Japan.
• Setmelanotide, a melanocortin-4 receptor agonist, is currently being evaluated in a global Phase 3 trial with topline data expected in Q2 2025, potentially offering the first therapy targeting the underlying biology of this disease.
• The designation follows similar status in Europe, strengthening Rhythm's global strategy to address significant unmet medical needs for patients with hypothalamic obesity caused by brain tumors, traumatic injury, stroke, or inflammation.
WEGOVY's Market Dominance Grows with Expanded Cardiovascular Indication and Strong Clinical Results
• Novo Nordisk's WEGOVY has secured FDA approval for cardiovascular risk reduction in March 2024, becoming the first obesity medication authorized to reduce cardiovascular death, heart attack, and stroke risks.
• Phase IIIb STEP UP trial demonstrates superior efficacy of WEGOVY 7.2mg compared to 2.4mg dosage, showing significant weight loss benefits at 72 weeks in adults with obesity.
• WEGOVY generated impressive US sales of $6.4 billion in 2024, with market presence now extending to over 15 global markets including recent approval in Japan.
Rhythm Pharmaceuticals Announces Positive IMCIVREE® Sales and Pipeline Advancements
• Rhythm Pharmaceuticals reports preliminary unaudited net revenues of approximately $42 million for Q4 2024 and $130 million for full year 2024 from global IMCIVREE® sales.
• Topline data from the Phase 3 trial of setmelanotide in acquired hypothalamic obesity (HO) is expected in the first half of 2025.
• A new Phase 2 trial exploring setmelanotide in Prader-Willi syndrome (PWS) is planned to commence in the first quarter of 2025.
• Enrollment is completed in the Phase 3 EMANATE trial substudies for genetically-caused MC4R pathway diseases, with topline data anticipated in H1 2026.
Novo Nordisk's Cagrilintide/Semaglutide Combo Shows Superior Weight Loss in Phase III Trial
• A fixed-dose combination of cagrilintide and semaglutide led to greater weight loss at 68 weeks compared to either drug alone or placebo in the REDEFINE 1 trial.
• The FDA expanded the indication for setmelanotide (Imcivree) to include children as young as 2 years with specific types of genetic obesity.
• Palatin Technologies reported that 71% of patients with type 2 diabetic nephropathy achieved a significant reduction in urine protein in a phase IIb study with bremelanotide.
FDA Expands Setmelanotide Approval to Include Children Aged 2-5 with Rare Obesity Forms
• The FDA has expanded the approval of setmelanotide (Imcivree) to include children aged 2 to 5 years with rare genetic forms of obesity.
• The expanded indication is based on the VENTURE phase 3 trial, which demonstrated significant BMI reduction in young children with POMC, LEPR deficiencies, and Bardet-Biedl syndrome.
• Setmelanotide is the first precision medicine to target the MC4R pathway, addressing the root cause of hyperphagia and obesity in these rare genetic conditions.
• The most common adverse events observed in clinical trials were mild to moderate, including skin hyperpigmentation and injection site reactions.
Rhythm Pharmaceuticals Targets Rare Obesity Disorders with Promising Treatments
Rhythm Pharmaceuticals Inc. is making strides in the treatment of rare obesity disorders, with its drug Imcivree showing significant revenue growth. Oppenheimer analysts are optimistic about the company's future, especially with upcoming Phase 3 trial results for hypothalamic obesity treatment and the potential expansion of Imcivree's uses.
FDA Gears Up for Year-End Decisions on Novel Therapies for Rare Diseases and Cancer
• The FDA is set to decide on Ionis Pharmaceuticals' olezarsen for familial chylomicronemia syndrome (FCS), a rare genetic disease, by December 19, following positive Phase III results.
• Lexicon Pharmaceuticals awaits the FDA's decision on sotagliflozin as an adjunct therapy for type 1 diabetes by December 20, despite concerns raised by an advisory committee.
• AstraZeneca and Daiichi Sankyo's Dato-DXd for non-squamous NSCLC is under FDA review, with a decision expected by December 20, based on Phase III data showing progression-free survival benefits.
• Neurocrine Biosciences anticipates FDA decisions on crinecerfont for congenital adrenal hyperplasia (CAH) by December 29 and 30, potentially marking the first new treatment in 70 years.
FDA Wraps Up 2024 with Key Approvals for Drugs Targeting Various Conditions
• The FDA approved Vertex's Alyftrek for cystic fibrosis, offering improved dosing and potential market exclusivity.
• Novo Nordisk's Alhemo was approved for hemophilia A and B, providing a new option for patients with inhibitors.
• Bristol Myers Squibb's Opdivo Qvantig gained approval as a subcutaneous formulation, offering faster administration for various solid tumors.
• Eli Lilly's Zepbound secured approval for obstructive sleep apnea in obese adults, marking the first prescription medicine for this condition.
Setmelanotide Shows Promise in Reducing Obesity in Young Children With Rare Genetic Deficiencies
• A Phase 3 trial of setmelanotide in children aged 2-5 years with Bardet-Biedl syndrome or POMC, PCSK1, or LEPR deficiency demonstrated clinically meaningful reductions in BMI Z-score.
• 83% of patients achieved a ≥0.2-point reduction in BMI Z-score after 52 weeks, with a mean percent change in BMI from baseline of -18%.
• Caregivers reported a 91% reduction in patient hunger compared to baseline, alongside a reduced personal burden.
• Setmelanotide was generally well-tolerated, with no new safety signals and common adverse events including skin hyperpigmentation and vomiting.
Rhythm Pharmaceuticals HR Chief Sells Shares Amid Positive Clinical and Financial Outlook
• Rhythm Pharmaceuticals' HR chief, Pamela Cramer, sold $585,940 worth of stock under a pre-established trading plan, while also exercising stock options.
• The company reported a 48% year-over-year increase in global net revenue in Q3 2024, driven by sales of IMCIVREE, and anticipates Phase III data for acquired hypothalamic obesity in early 2025.
• Rhythm is advancing its clinical programs, expecting to complete enrollment in multiple trials by year-end and initiate dosing for new indications in early 2025.
• Despite not being profitable over the last twelve months, Rhythm Pharmaceuticals boasts impressive gross profit margins and strong stock performance, with a 133.08% price increase over the past year.
Rhythm Pharmaceuticals Reports Strong Q3 2024 Driven by IMCIVREE Sales, Advances Hypothalamic Obesity Program
• Rhythm Pharmaceuticals reported a 48% year-over-year increase in global net revenue, reaching $33.3 million in Q3 2024, driven by IMCIVREE sales for Bardet-Biedl Syndrome (BBS).
• The company is advancing its clinical programs, with topline data from a Phase III trial for acquired hypothalamic obesity expected in the first half of 2025.
• A PDUFA date for expanding IMCIVREE's label to include children ages two to six is set for December 26, 2024, potentially expanding the patient opportunity.
• Rhythm anticipates sufficient cash to fund operations into 2026, with reduced operating expense guidance for 2024.
FDA Grants Priority Review for Setmelanotide sNDA in Young Children with Rare Genetic Obesity
• The FDA has accepted Rhythm Pharmaceuticals' sNDA for setmelanotide, seeking approval for children aged 2-6 with obesity due to Bardet-Biedl syndrome or POMC/LEPR deficiency.
• The sNDA is supported by Phase 3 trial data showing a 3.04 mean reduction in BMI-Z score and an 18.4% mean reduction in BMI with setmelanotide treatment.
• The FDA has granted Priority Review with a PDUFA goal date of December 26, 2024, potentially offering a precision therapy for young patients with rare MC4R pathway diseases.
• Setmelanotide is currently approved for patients 6 years and older with specific genetic obesity conditions, and this expansion could positively affect younger children and their families.
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