Rhythm’s Setmelanotide Hits Big in Rare Obesity Trial

Rhythm Pharmaceuticals just shared some big news that could be a game-changer for patients living with acquired hypothalamic obesity — a rare and serious condition that can happen after damage to the hypothalamus, often from brain tumors or treatments like surgery or radiation. The company announced that its Phase 3 TRANSCEND trial met its primary endpoint, showing that their MC4R agonist, setmelanotide, led to a highly significant and meaningful reduction in BMI compared to placebo.

Here’s a quick snapshot of the key results:

• -16.5% average BMI reduction in patients on setmelanotide, vs +3.3% in the placebo group at 52 weeks — that’s a 19.8% placebo-adjusted difference.

• 80% of patients on the drug hit a BMI reduction of 5% or more — a promising sign for durable, clinically meaningful weight loss.

• The drug also helped reduce hunger scores and improve BMI Z-scores in pediatric patients.

On the safety side, it was generally well-tolerated with no new concerns. The most common side effects were things like nausea, vomiting, diarrhea, and mild injection site reactions — consistent with what’s already known about the drug.

Experts are calling this a breakthrough, given how limited current treatment options are for this condition. David Meeker, CEO of Rhythm, said these results could lead to setmelanotide becoming the first-ever approved therapy for acquired hypothalamic obesity. The company is now preparing for FDA and EMA submissions in the third quarter of 2025.

If approved, this could be a major step forward — not just for patients, but for the broader use of MC4R-targeted therapies in rare neuroendocrine diseases.