Rhythm Pharmaceuticals reported long-term setmelanotide and one-year bivamelagon data at ENDO 2026, showing sustained weight loss and hunger reductions in acquired hypothalamic obesity, alongside real-world benefits in Bardet-Biedl syndrome.
Written By: Farha Farheen, PharmD
Reviewed By: Pharmacally Editorial Team
Rhythm Pharmaceuticals presented new clinical and real-world findings at the Endocrine Society’s Annual Meeting (ENDO 2026), highlighting the long-term impact of its MC4R-targeted therapies across acquired hypothalamic obesity (HO), Bardet-Biedl syndrome (BBS), and Prader-Willi syndrome (PWS).
The presentations included 2.5-year data from a Phase 2 study and long-term extension of setmelanotide in acquired HO, one-year Phase 2 results for oral MC4R agonist bivamelagon, and real-world analyses of setmelanotide in BBS.
Targeting MC4R Pathway Disorders
MC4R pathway diseases disrupt appetite regulation, causing severe hyperphagia and obesity that often respond poorly to conventional treatments. Setmelanotide, a selective MC4R agonist, is already approved for several rare genetic obesity disorders, while bivamelagon is an investigational oral MC4R agonist under development.
Long-Term Setmelanotide Results in Acquired HO
An oral presentation led by Christian Roth, MD, evaluated patients with acquired HO who received setmelanotide for up to 2.5 years. Across all 11 participants, setmelanotide achieved a mean BMI reduction of 18.9% from baseline and a mean decrease in BMI z-score of 1.60. Patients most commonly experienced nausea, skin hyperpigmentation, upper respiratory tract infection, and vomiting.
Additional analyses showed weight-category improvements after one year. More than 70% of pediatric and adult patients improved by at least one weight category, while roughly half improved by two or more categories. No placebo-treated patients achieved a two-category improvement.
A post-hoc subgroup analysis examined patients with prior bariatric surgery. Among three patients treated with setmelanotide, BMI reductions ranged from 9.6% to 37.9% after one year, compared with a 4.8% BMI increase in the single placebo-treated patient.
Oral Bivamelagon Shows Continued BMI Reductions
Phase 2 data from 26 patients with acquired HO showed progressive BMI declines after 52 weeks of oral bivamelagon treatment. BMI fell 6.7–16.6% across treatment cohorts, with the largest effect observed among patients receiving 600 mg throughout the study. Hunger scores improved across all groups, while pediatric patients also demonstrated reductions in BMI z-scores.
The most commonly reported adverse events were vomiting, nausea, diarrhea, and headache.
Real-World Data Support Setmelanotide in BBS
A retrospective U.S. analysis involving 286 patients with BBS found that 62% of adults achieved at least 10% body weight loss after 12 months of setmelanotide treatment. Mean body weight decreased by 9.8% among adults and 7.8% across all patients.
Outpatient obesity-related visits declined significantly following treatment initiation, suggesting healthcare utilization benefits beyond weight loss. Investigators noted that later initiators began therapy with higher baseline weight and BMI than patients who started treatment earlier.
Interim results from the RESTORE study showed sustained reductions in hyperphagia-related symptoms over six months. Participants reported fewer hunger-driven behaviors, reduced nighttime hunger episodes, and decreased use of other anti-obesity medications.
Implications for Rare Obesity Disorders
The ENDO 2026 presentations add to growing evidence supporting MC4R agonism across rare obesity disorders characterized by severe hyperphagia and persistent weight gain. Together with recently reported six-month Phase 2 results of setmelanotide in Prader-Willi syndrome, the findings strengthen Rhythm’s expanding portfolio across rare neuroendocrine and genetic obesity disorders.
Further studies and long-term follow-up will help define the durability of treatment effects and support potential expansion into additional MC4R pathway diseases, underscoring Rhythm’s leadership in rare obesity therapeutics.
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About the Writer
Farha Farheen, PharmD (LinkedIn) is a pharmacy professional with a strong interest in pharmacovigilance and clinical research. She has completed her Doctor of Pharmacy (Pharm.D) along with her internship as a Clinical Pharmacist. She has hands-on experience in adverse drug reaction (ADR) reporting, safety data documentation, and pharmacovigilance workflows, and is proficient in using VigiFlow. She is also a patent holder for an antibacterial formulation enriched with bioactive substances, granted by the German Patent and Trademark Office.