Vanda Pharmaceuticals acknowledged today that the FDA has refused to approve its marketed non-24-hour sleep-wake disorder drug Hetlioz® (tasimelteon) for an additional indication of jet lag disorder (JLD), instead rejecting the company’s supplemental NDA (sNDA).

Vanda said it received a Complete Response Letter (CRL) from the FDA despite showing in the Phase II proof-of-concept JET Study (VP-VEC-162-2102; NCT03291041) that JLD patients treated with Hetlioz reported sleeping nearly three hours longer over the three nights following their trip from the U.S. to the U.K. compared with people not receiving the melatonin receptor agonist.

However, only 25 patients participated in the JET study, of which 13 were treated with Hetlioz, and 12 with placebo: “Due to the complexity of the study, the study was terminated before it reached the original enrollment goal of 90 patients,” Vanda stated May 23, 2018, in trumpeting results from the JET Study.

The 25-patient population is only half the 50-patient enrollment anticipated by Vanda when it first posted information about the JET Study on ClinicalTrials.gov on September 20, 2017.

“In the CRL, the FDA asserted that these measures demonstrating improved sleep are of unclear clinical significance,” Vanda said in a statement. “Vanda is perplexed by this conclusion.”

The company cited the inclusion of disturbed sleep and daytime sleepiness as essential features of JLD by the American Academy of Sleep Medicine, as well as what it called the recognition by travelers of disrupted nighttime sleep and/or sleepiness during the day stemming from rapid travel across time zones.

The CRL “contains additional observations on various aspects of Vanda’s sNDA,” Vanda added, without disclosing any of them.

‘Deeply Disappointed’

“We are deeply disappointed to have not received approval at this time, given our previous discussions with the FDA on this program,” Vanda President and CEO Mihael H. Polymeropoulos, MD, stated.

Vanda signaled a potential FDA rejection last month. In announcing second-quarter results, Vanda disclosed that on July 19, it received a “Deficiencies Preclude Discussion” letter from the FDA—but added that the letter did not specify any deficiencies on file at that time.

“We will wait to hear what the potential deficiencies are and work expeditiously with the FDA toward a successful resolution,” Polymeropoulos told analysts July 31 on the company’s quarterly earnings call, according to a transcript published by The Motley Fool.

Despite the FDA “deficiencies” letter, Vanda kept its original guidance to investors as forecast on February 13, in which the company projected 2019 net product sales of Hetlioz of between $137 million and $143 million.

Hetlioz is Vanda’s top-selling drug, generating net product sales of $66.792 million in the first half of 2019, up nearly 25% from $53.468 million in January-June 2018. For all of last year, Hetlioz racked up $115.835 million, up nearly 29% from $89.978 million in 2017.

The FDA approved Hetlioz for the treatment of non-24-hour sleep-wake disorder (non-24) in January 2014.

In today’s statement, Polymeropoulos said Vanda remained committed to obtaining FDA marketing approval for Hetlioz in JLD. Hetlioz is also in Phase III development for Smith-Magenis syndrome and non-24 pediatric —as well as in Phase II development for delayed sleep phase disorder.

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