Rhythm Pharmaceuticals has announced positive top-line results from its pivotal Phase III TRANSCEND trial evaluating Imcivree (setmelanotide) in patients with acquired hypothalamic obesity, showing substantial weight loss that could potentially expand the drug's market reach.
The global, placebo-controlled, double-blind, randomized trial met its primary endpoint, demonstrating a statistically significant and clinically meaningful reduction in body mass index (BMI) in both adult and pediatric patients with hypothalamic obesity compared to placebo over 52 weeks of treatment.
Patients treated with Imcivree achieved a 16.5% reduction in BMI from baseline, while those on placebo experienced a 3.3% increase, resulting in a 19.8% placebo-adjusted reduction. Notably, 83% of patients receiving the melanocortin-4 receptor (MC4R) agonist achieved a BMI reduction of 5% or greater at the 52-week mark.
Understanding Hypothalamic Obesity
Acquired hypothalamic obesity is a rare form of obesity resulting from damage to the hypothalamus, often due to brain tumors or their treatment. The condition leads to accelerated weight gain, hyperphagia (excessive hunger), and reduced energy expenditure.
"There is an urgent need for effective treatments as current approaches, including lifestyle interventions and pharmacotherapy intended for general obesity, have shown limited effectiveness in achieving long-term, durable weight loss," explained Dr. Susan Phillips, pediatric endocrinologist at Rady Children's Hospital-San Diego.
The hypothalamus plays a critical role in regulating hunger and metabolism through the melanocortin-4 receptor pathway. Imcivree works by activating this pathway, acting as a replacement for alpha-melanocyte-stimulating hormone (α-MSH) to help restore normal weight regulation.
Secondary Endpoints and Safety Profile
The trial also showed improvements across key secondary endpoints, including a 1.4 placebo-adjusted mean reduction in the weekly average of daily maximal hunger scores for patients 12 years and older, addressing the hyperphagia component of the condition.
Imcivree maintained a favorable safety profile consistent with previous studies. The most common treatment-emergent adverse events included nausea, vomiting, diarrhea, injection site reactions, headache, and skin hyperpigmentation. Importantly, no serious adverse events leading to study discontinuation were reported during the trial.
Regulatory Strategy and Market Potential
Based on these positive results, Boston-based Rhythm Pharmaceuticals plans to file for regulatory approval with both the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) in the third quarter of 2025.
Imcivree is already approved for weight management in patients with certain genetic obesity disorders. In the United States, it's indicated for patients aged two years and older with obesity due to Bardet-Biedl syndrome (BBS) or deficiencies in Pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR). Similar approvals exist in Europe and the UK.
Oppenheimer analyst Leland Gershell projects that adding hypothalamic obesity to Imcivree's label could help the drug exceed $1 billion in annual sales by 2028. GlobalData forecasts even higher potential, predicting the drug will reach blockbuster status in 2030 with annual sales of $1.23 billion, a significant increase from last year's estimated sales of $130 million.
Administration and Mechanism of Action
Imcivree is administered as a subcutaneous injection and functions as an MC4R agonist. The drug acts in place of naturally occurring α-MSH to activate the MC4 receptor, helping to regulate hunger and energy expenditure in patients whose natural pathway is disrupted.
Rhythm Pharmaceuticals, which currently has a market capitalization of $2.9 billion, plans to present the complete data from the TRANSCEND study at an upcoming medical meeting, where additional details on the drug's efficacy and safety profile are expected to be shared.
