FDA Okays Hetlioz (Tasimelteon) for Sleep Disorder in Blind

Susan Jeffrey

January 31, 2014

The US Food and Drug Administration (FDA) has approved tasimelteon (Hetlioz, Vanda Pharmaceuticals Inc) for the treatment of non–24-hour sleep-wake disorder (non-24), the first such drug approved for this condition, the agency announced today.

Non-24 is a chronic circadian rhythm disorder that disrupts the sleep-wake cycle and affects the majority of totally blind individuals. Without input from the eyes, information about environmental light levels fails to reach the suprachiasmatic nuclei in the hypothalamus to synchronize the internal clock.

As a result, levels of the hormone melatonin, produced by the pineal gland and playing a key role as a feedback regulator of the master circadian clock, peak at later and later times each day, disrupting the sleep-wake cycle.

Although most people who are totally blind still can perceive light well enough to prevent non-24, it's estimated that as many as 100,000 individuals in the United States have this condition; they can't perceive enough light to establish a normal night sleep schedule, the FDA notes in a release. Non-24 can occur at any age.

"Non-24-hour sleep-wake disorder can prevent blind individuals from following the normal daily schedule that we all take for granted," said Eric Bastings, MD, deputy director of the Division of Neurology Products in the FDA's Center for Drug Evaluation and Research, in a statement from the FDA. "Hetlioz can improve the ability to sleep at night and to be active during the day."


Approval was based on results of 2 trials: the Safety and Efficacy of Tasimelteon (SET) trial, a 26-week study that included 84 patients, and the Randomized Withdrawal study of the Safety and Efficacy of Tasimelteon (RESET), a 19-week trial that included 20 patients, all of whom had been previously screened during the SET trial, and "entrained" during open-label tasimelteon treatment.

"Entrainment" of the circadian rhythm, as measured by urinary 6-hydroxymelatonin sulfate (aMT6s), a main metabolite of melatonin, was the primary efficacy endpoint for SET. Scores on the 24-hour Clinical Response Scale was another defined endpoint for SET. Outcomes for RESET included maintenance of entrainment (aMT6s) and maintenance of clinical response.

Study results demonstrated that tasimelteon entrains the master clock (both melatonin and cortisol) and has clinically meaningful effects on the sleep-wake cycle in terms of the timing and amount of sleep, and improved measure of global functioning.

Tasimelteon was reviewed by the FDA under priority review that provides for an expedited review of drugs that treat serious conditions and have the potential to provide significant improvement in safety or effectiveness of the treatment, diagnosis, or prevention of such serious conditions, the FDA statement notes. It also received orphan-product designation because it is intended to treat a rare disease or condition.

The drug was also reviewed on November 20, 2013, by the FDA's Peripheral and Central Nervous System Drugs Advisory Committee. The committee agreed, almost unanimously, that the drug had been proven to be effective and safe for patients with non-24.

The most common adverse reactions in the clinical trials were headache, increased alanine aminotransferase, nightmares or unusual dreams, and upper respiratory or urinary tract infection. After taking tasimelteon, patients should limit their activity to preparing for going to bed because the drug can impair the performance of activities requiring complete mental alertness, the company notes in their release.

The drug should be avoided in combination with fluvoxamine or other strong CYP1A2 inhibitors, the company notes, because of a potentially large increase in exposure to tasimelteon and a greater risk for adverse reactions. It should also be avoided in combination with rifampin or other CYP3A4 inducers because of a potentially large decrease in exposure to tasimelteon with reduced efficacy, the release adds.

There are no adequate or well-controlled studies in pediatric patients, those with hepatic impairment, or pregnant women, and the statement notes that on the basis of animal data, tasimelteon may cause fetal harm. Therefore, it "should be used during pregnancy only if the potential benefit justifies the potential risks." Caution should also be used in nursing women.

"Totally blind people have struggled with the problems brought on by non-24-hour sleep-wake disorder, sometimes for their entire life, without understanding what causes it and without being able to do anything about it," said Steven W. Lockley, PhD, Division of Sleep Medicine, Brigham and Women's Hospital, a teaching affiliate of Harvard Medical School in Boston, Massachusetts, in the company statement. "Today's FDA approval of Hetlioz means that, for the first time, these patients have access to an approved, safe and effective treatment for their difficult debilitating disorder."

"The FDA approval of Hetlioz would not have been accomplished without the heroic efforts of blind patients and their advocates," said Mihael H. Polymeropoulos, MD, Vanda's president and chief executive officer. "We are committed to providing much needed support to patients with non-24 and facilitating access to this new therapeutic option."

Vanda anticipates making tasimelteon 20-mg capsules commercially available in the second quarter of 2014.

Full prescribing information can be found at www.hetlioz.com.


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