FDA Approves Hetlioz for Sleep Disturbances in Smith-Magenis Syndrome Patients

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by Marta Figueiredo |

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Hetlioz (tasimelteon) has been approved in the U.S. to treat nighttime sleeping problems in people, ages 3 and older, with Smith-Magenis syndrome (SMS), a rare genetic disorder also linked to obesity.

The 20 mg capsule formulation — already approved to treat a sleep disorder called non-24-hour sleep-wake disorder — will be immediately available to SMS patients 16 years and older, while its new liquid formulation, supplied as 4 mg/mL in 48 mL and 158 mL bottles, is expected to be available in the first months of 2021 to patients ages 3 to 15, said the therapy’ developer Vanda Pharmaceuticals.

“We are very excited to see HETLIOZ, the first ever treatment approved for people with SMS, addressing the significant problem of sleep disturbances and we are happy to see this treatment used in our community,” Maggie Miller, co-founder and vice president of PRISMS (Parents and Researchers Interested in SMS), said in a press release.

“We thank Vanda and the [U.S. Food and Drug Administration (FDA)] for partnering to help our community and we look forward to continued partnership to bring this important therapy to families with SMS,” she added.

The decision comes four months after the FDA granted priority review to Vanda’s separate requests for approval of each Hetlioz formulation. The first request which included both formulations had been rejected by the agency early this year.

Hetlioz previously received the FDA’s orphan drug designation for the treatment of SMS, which provides regulatory support and financial benefits, as well as a seven-year marketing exclusivity period in the U.S. upon approval.

The therapy works by activating two brain receptors of melatonin, a hormone that induces sleepiness and helps regulate a person’s biological clock — known as a circadian rhythm. Melatonin also regulates the breakdown of fat tissue.

Besides sleep disturbances — such as difficulties falling asleep or frequent, prolonged nighttime awakenings — the common symptoms of SMS include characteristic facial features, intellectual disability, speech and motor delays, and behavioral problems. Obesity is seen in a significant proportion of patients with SMS, starting in childhood.

The disorder is thought to be mainly associated with genetic abnormalities involving the RAI1 gene, which regulates the activity of a number of genes from the melanocortin-4 receptor pathway. This pathway is involved in appetite regulation, controlling hunger, and satiety or feeling full.

The approval was based on data from a Phase 2/3 clinical trial (NCT02231008) in SMS patients, 16 to 65 years old. Results showed that Hetlioz significantly improved patients’ overall sleep quality and total nighttime sleep duration, compared with a placebo, meeting the study’s main goals.

Hetlioz’s safety profile was similar between pediatric and adult SMS patients, and was consistent with that reported in previous trials of people with non-24-hour sleep-wake disorder.

The treatment’s approval “would not have been accomplished without the heroic efforts of SMS patients and the efforts of their families and advocates supporting the recruitment, design, and conduct of the study,” said Mihael H. Polymeropoulos, MD, Vanda’s president and CEO.

In a longer, open-label study, Hetlioz treatment for about six months resulted in significant improvements in SMS patients’ sleep quality and behavior, compared with before treatment.

According to Hetlioz’s label, the therapy is meant to be taken one hour before bedtime, at the same time every night. The recommended daily dose for patients 16 and older is one 20 mg capsule, while the dose for younger patients depends on their weight — 0.7 mg/kg of Hetlioz for those weighing up to 28 kg (about 61.7 pounds) and 20 mg for heavier patients.

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