FDA Grants Priority Review to Sleep Disorder Therapy Hetlioz for Smith-Magenis Syndrome

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by Marta Figueiredo |

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The U.S. Food and Drug Administration (FDA) has accepted and given priority review to Vanda Pharmaceuticals’ request seeking the approval of Hetlioz (tasimelteon) as a treatment for people with Smith-Magenis syndrome (SMS), a rare genetic disorder characterized by sleeping problems and often associated with obesity.

Sold in 20 mg capsules, Hetlioz currently is approved for the treatment of non-24-hour sleep-wake disorder, known as N24. In this disorder, a person’s biological clock — known as a circadian rhythm — fails to synchronize to a 24-hour day, disrupting normal sleeping patterns. N24 occurs in 55-70% of completely blind people, but also affects an unknown number of sighted individuals.

Vanda filed a supplemental new drug application (sNDA) seeking to change Hetlioz’s label on its capsule formulation to include adults with SMS. The biopharmaceutical company also submitted a new drug application for the treatment’s liquid formulation to treat children with the disease.

This is the second time Vanda has sought Hetlioz’ approval for this condition. The FDA rejected the company’s first sNDA — which combined both formulations — in March. In a meeting with the FDA, held in May, Vanda was able to resolve the outstanding issues regarding the first application.

The FDA has set a Prescription Drug User Fee Act action date for Dec. 1, meaning that a decision is due by then. Hetlioz previously received the FDA’s orphan drug designation for the treatment of SMS. Currently, there are no approved treatments for this complex developmental disorder.

“The FDA filing of the HETLIOZ applications for priority review marks a major milestone and brings us closer to providing a critical therapy to patients with SMS,” Mihael H. Polymeropoulos, MD, Vanda’s president and CEO, said in a press release.

Hetlioz works by binding to and activating two brain receptors of melatonin, a hormone that promotes sleepiness and helps regulate a person’s circadian rhythm. Melatonin also is known to play a central role in the breakdown of fat tissue to lower body weight.

Sleep disturbances — such as difficulties falling asleep or frequent, prolonged nighttime awakenings — are among SMS’ major symptoms. Others include characteristic facial features, varying degrees of intellectual disability, speech and motor delays, and behavioral problems.

A considerable proportion of SMS patients also gain excessive weight and become obese.

Most SMS cases are caused by a deletion of a small portion of the human chromosome 17, which includes the RAI1 gene, believed to play a major role in the disorder’s development.  In rarer cases, the disease is caused by single RAI1 mutations.

RAI1 regulates the activity of a number of genes from the melanocortin-4 receptor (MC4R) pathway, which is involved in appetite regulation, controlling hunger and satiety (feeling full).

Data from a Phase 2/3 clinical trial (NCT02231008) — the largest placebo-controlled study ever conducted in SMS patients — showed that Hetlioz led to significant improvements in overall sleep quality and total nighttime sleep duration, meeting the trial’s main goals.

The benefits in sleep were consistent across patients with chromosomal deletions of various lengths and in an individual with a RAI1 mutation.

In a longer, open-label study, Hetlioz treatment for about 27 weeks resulted in significant improvements not only in the SMS patients’ sleep quality, but also in behavior, compared with baseline (before treatment).

Heltioz also is being evaluated in Phase 3 clinical trials as a potential treatment for children with non-24-hour sleep-wake disorder and for people with delayed sleep phase disorder. In this disorder, a person’s sleep is delayed by two hours or more beyond what is considered an acceptable or conventional bedtime. The delayed sleep then causes difficulty in being able to wake up at the desired time.

Vanda’s application for Hetlioz as a treatment for jet lag disorder, also known simply as jet lag, was rejected by the FDA in August 2019, with the agency stating that measures demonstrating improved sleep were of unclear clinical significance. The company continues to work toward the medicine’s approval for this indication.

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