Hetlioz (tasimelteon) will not gain an expanded EU indication for Smith-Magenis syndrome after the European Medicines Agency (EMA) upheld its earlier rejection following reexamination.

The rejected application sought to extend use of the circadian-rhythm drug to treat nighttime sleep disruptions in adults and children aged 3-15 years with Smith-Magenis syndrome. After reassessing the file in March 2026, the EMA maintained its initial December 2025 decision, citing continued concerns about study methodology, statistical analysis, trial conduct, and the adequacy of pediatric safety data.

Smith-Magenis syndrome is a rare hereditary disorder characterized by developmental delays, behavioral problems, and sleep disruptions. Sleep issues in affected individuals result from abnormal melatonin production patterns. 

The EMA had previously designated Hetlioz as an orphan medicine for Smith-Magenis syndrome treatment in May 2023, recognizing its potential for this rare condition.

Current Indication and Mechanism 

Hetlioz is currently used to treat totally blind adults with non-24-hour sleep-wake disorder, a condition in which sleep patterns become desynchronized with day and night cycles. The drug contains tasimelteon, which acts on the same receptors as melatonin to promote sleep and regulate circadian rhythms. Melatonin normally rises after darkness onset and peaks during nighttime hours, coordinating the body’s sleep cycle through specific brain cell interactions.

Clinical Evidence and Safety Concerns 

Vanda Pharmaceuticals Netherlands B.V. submitted results from a study involving 26 participants with Smith-Magenis syndrome experiencing nighttime sleep disruptions. The trial included 11 children aged 3-15 years and 15 adults and adolescents aged 16 years or older and compared the effects of tasimelteon vs placebo over 4 weeks. Researchers measured effectiveness through caregiver-assessed improvements in nighttime sleep quality and total sleep duration using postsleep questionnaires.

Tasimelteon improved nighttime sleep in patients with Smith-Magenis syndrome, with significant gains in caregiver-reported sleep quality and modest increases in total sleep time compared with placebo. Benefits were supported by both subjective and actigraphy-based measures. The treatment was generally well tolerated over the short study period.

The EMA identified multiple concerns regarding study methodology, statistical analysis approaches, and trial conduct that created uncertainties about observed treatment effects. Safety evaluation in children with Smith-Magenis syndrome remained inadequately investigated due to study design limitations and implementation issues. These persistent concerns about benefit-risk assessment in the pediatric population aged 3-15 years led to the sustained rejection. 

The current authorization for non-24-hour sleep-wake disorder in blind adults remains unaffected by this decision.