Ashley Shoemaker, MD, MSci, discusses leveraging setmelanotide in acquired hypothalamic obesity

In a recent video discussion with Contemporary Pediatrics, Ashley Shoemaker, MD, MSci, associate professor of pediatrics and pediatric endocrinology at Vanderbilt Health, shared critical insights into the evolving landscape of diagnosing and managing rare genetic obesity disorders.

The focus of the conversation centered on the recent FDA approval of setmelanotide (Imcivree; Rhythm Pharmaceuticals), which represents a significant milestone as the first targeted therapy for acquired hypothalamic obesity in patients 4 years and older. This condition, often resulting from rare genetic mutations or injury to the hypothalamus, has historically been difficult to treat, leaving clinicians and families with few effective options beyond standard lifestyle interventions that rarely address the underlying biological drivers of the disease.

Shoemaker emphasized that diagnosing these rare disorders remains a significant challenge, with one of the primary pitfalls being the delay in identifying the specific genetic or physiological cause of a child’s rapid weight gain. She noted that early and proactive management is essential because these conditions are often characterized by insatiable hunger, known as hyperphagia, which is driven by a disruption in the MC4R pathway.

When pediatricians encounter patients with early-onset, severe obesity that does not respond to typical interventions, it is crucial to consider specialized genetic testing or screening for hypothalamic injury. Missing these underlying causes can lead to years of ineffective treatment and the progression of comorbidities.

With the introduction of setmelanotide, the role of the pediatrician has expanded to include critical longitudinal monitoring for those on this new therapy. While subspecialists such as pediatric endocrinologists typically handle the initial prescription and titration of setmelanotide, the pediatrician serves as the essential frontline observer. Shoemaker highlighted that pediatricians should be vigilant in monitoring for changes in linear growth and potential adverse effects.

Common reactions to watch for include skin hyperpigmentation, nausea, vomiting, and headaches. Furthermore, because of the medication’s impact on the hormonal and neurological systems, clinicians must be alert for serious safety signals such as acute adrenal insufficiency or sodium imbalances, particularly in patients with existing hormonal deficiencies.

Beyond clinical metrics, Shoemaker underscored the importance of the pediatrician’s role in assessing the patient’s psychological well-being. Depression and suicidal ideation have been reported in association with setmelanotide across various indications, requiring consistent screening during routine visits.

The pediatrician acts as a vital conduit for families, ensuring that any subtle changes in behavior or mood are reported back to the subspecialty team. By providing this integrated care, pediatricians help ensure that the first-of-its-kind approval for hypothalamic obesity translates into safe and meaningful long-term outcomes for their patients.

Relevant disclosures for Shoemaker include Rhythm Pharmaceuticals and Chiesi USA.

Reference

Rhythm Pharmaceuticals announces FDA approval of Imcivree (setmelanotide) for patients with acquired hypothalamic obesity. News release. Rhythm Pharmaceuticals. March 19, 2026. Accessed March 19, 2026. https://ir.rhythmtx.com/news-releases/news-release-details/rhythm-pharmaceuticals-announces-fda-approval-imcivreer-1