Tasimelteon Reduces Transient Insomnia After Acute Sleep-Time Shift

Susan Jeffrey

December 04, 2008

December 4, 2008 — Randomized trial results with tasimelteon, a melatonin agonist, suggest that the still-investigational agent improves sleep initiation and maintenance in concert with an acute shift in endogenous circadian rhythms after an abrupt advance in sleep time.

The findings suggest that tasimelteon might be useful in treating transient insomnia associated with circadian-rhythm sleep disorders, such as that caused by jet lag or in night-shift work, the researchers conclude.

"We were really excited and encouraged by the findings," lead author Shantha M. W. Rajaratnam, PhD, from the division of sleep medicine at Brigham and Women's Hospital and Harvard Medical School, in Boston, Massachusetts, told Medscape Neurology & Neurosurgery. In particular, he noted, total sleep time in the phase 2 study was improved from 13 to 104 minutes, depending on the dose, with a dose-response effect.

"I think any sleep physician would realize that 104 minutes — more than an hour and a half of extra sleep — is an enormous improvement," Dr. Rajaratnam said. "It suggests that melatoninlike therapies can be very powerful in this context of circadian-rhythm sleep disorders."

 

Their report appears online December 2 ahead of publication in the Lancet. The study was funded by Vanda Pharmaceuticals.

Melatonin Agonists

Circadian-rhythm sleep disorders are common causes of insomnia affecting millions of people, particularly those who work at night or cross multiple time zones during travel, the authors write. Circadian-rhythm sleep disorders are characterized by persistent and recurrent sleep disturbances, insomnia, and excessive sleepiness when purposely awake. These disturbances occur when scheduled or desired sleep times are at odds with the endogenous circadian rhythms generated by the hypothalamic suprachiasmatic nuclei.

"The best possible treatment for patients with circadian-rhythm sleep disorders would simultaneously improve sleep and facilitate circadian readjustment," the authors write. Melatonin, a hormone produced by the pineal gland mainly during the "biological night," is involved in the circadian regulation of sleep and wake and has its effect through the melatonin MT1 and MT2 receptors.

Although melatonin is a popular treatment for patients with circadian-rhythm sleep disorders, the potency, purity and safety of melatonin products in the United States are not regulated by the Food and Drug Administration, the authors write. Meta-analyses have come to conflicting conclusions about the efficacy of melatonin, and there is little incentive for funders to do a definitive randomized trial.

"That's probably 1 of the big limitations to comparing the proprietary compounds with the naturally occurring hormone," Dr. Rajaratnam said. "It's difficult to find a funding opportunity to do that." The controversy about the efficacy of melatonin remains, in part, he said, because large-scale clinical trials are lacking. He and his colleague at Brigham & Women's Hospital, senior author Elizabeth B. Klerman, MD, "saw this as a really good opportunity to test a compound that we know is going to target those receptors in a larger-scale study."

Another melatonin agonist, ramelteon (Rozarem, Takeda Pharmaceuticals), was the first of these drugs that target MT1 and MT2 receptors to be approved. The advantage to studying these melatonin agonists is that each has a slightly different binding affinity to these melatonin receptors, he added. "The more compounds we have that have slightly different binding affinities, the more likely we'll be able to understand the physiological role of melatonin as well."

In the current paper, Dr. Rajaratnam and colleagues report results of a phase 2 study of tasimelteon to look at efficacy and the physiological mechanism, followed up with a phase 3 trial to confirm the efficacy of the new drug for the treatment of transient insomnia associated with an experimental shift in sleep phase meant to simulate first-night jet lag.

In the phase 2 study, 39 healthy subjects were randomized to tasimelteon in doses of 10, 20, 50, or 100 mg or to placebo. Each was monitored using polysomnography for 7 nights, 3 as a baseline measure, 3 nights after a 5-hour advance of the sleep-wake schedule with treatment before sleep, and 1 night after treatment. Plasma melatonin concentration was measured serially for circadian-phase assessment.

They report that subjects taking tasimelteon showed reduced sleep latency and increased sleep efficiency compared with those taking placebo. There was also a shift in the rhythm of plasma melatonin that was dose-dependent and occurred rapidly. "We showed, particularly for the highest doses, that the shift in body clock is occurring almost immediately after the compound is taken," Dr. Rajaratnam noted. "At the highest doses of tasimelteon, it was a shift of between 2 and 2.5 hours, so it was pretty remarkable."

 

In the phase 3 trial, 411 healthy subjects were randomized to receive 20, 50, or 100 mg of tasimelteon or placebo, after having transient insomnia induced in a sleep clinic by a 5-hour advance of the sleep-wake schedule. Treatment with tasimelteon was associated with significant improvements in sleep latency, sleep efficiency, and wake after sleep onset (sleep maintenance).

Phase 3 Results: Tasimelteon vs Placebo

Sleep Parameter Placebo Tasimelteon 20 mg Tasimelteon 50 mg Tasimelteon 100 mg
Sleep efficiency (%) 66.1 73.2 76.0 72.3
Total sleep time (min) 317.0 350.5 364.9 347.0
Wake after sleep onset (min) 140.3 116.2 106.3 122.3
Latency to sleep onset (min) 21.9 10.9 7.8 9.7
Latency to persistent sleep (min) 44.6 23.1 18.5 22.0

The frequency and severity of adverse events were similar between the placebo and tasimelteon groups. The most frequent adverse events were decreased hemoglobin concentration and hematocrit, probably from serial blood sampling; intravenous site pain, irritation, and bruising; somnolence (in the phase 2 study); nausea (in the phase 3 trial); and headache (in both studies), the authors note.

"In both studies, we did cognitive testing of participants to see whether there was any impairment or residual effect of treatment, and we could not find any," Dr. Rajaratnam noted.

An important next step, he said, is to look at the effects of chronic shifting of the biological clock with tasimelteon. "Because there is now considerable evidence that disruption of the circadian system is linked with adverse metabolic, cardiovascular, and other end points, the ideal study would be to do chronic administration of tasimelteon in a shift-worker population or something like that, measuring those types of outcomes to see if there's any improvement," he said.

Study of other chronic conditions, such as delayed sleep phase syndrome, would also be obvious candidates for study, he added.

A release from Vanda Pharmaceuticals notes that "additional clinical trials will have to be conducted to examine the role of circadian regulators in the treatment of other disorders such as depression, nondipper hypertension, and others."

 

Important Educational Goal

Daniel P. Cardinali, MD, PhD, from the School of Medicine, University of Buenos Aires, in Argentina, and Diego A. Golombek, PhD, from the National University of Quilmes, also in Buenos Aires, authored a Commentary accompanying the paper. In it, they point out that 1 of the main strengths of this paper is evident in its title, "after sleep-time shift." "The findings clearly show the chronobiotic function of melatonin agonists — ie, drugs that move the hands of the circadian clock, thus phase-shifting key markers of biological rhythms (eg, core temperature, locomotor activity, plasma melatonin concentrations)," the editorialists write.

However, it is important to make the distinction that melatonin analogs are not standard hypnotic drugs resembling benzodiazepines and their derivatives, they write. Compared with benzodiazepines, these melatoninlike compounds have a modest sleep-promoting effect, working rather by amplifying day-night differences in alertness and sleep quality.

"In view of the negative effects of benzodiazepines (addiction, dependence, etc) and the absence of these negative effects with melatonin analogs, an important educational goal for public-health authorities is to change the opinion of consumers about the validity of any sleep-promoting therapy," Drs. Cardinali and Golombek write. "Until this change in expectation is achieved, the dropout rate with melatonin analogs will probably continue to be high."

Asked for his response to the points made in the editorial, Dr. Rajaratnam acknowledged that in retrospect, they perhaps should have made the difference between melatonin-based medications and traditional hypnotics clearer in the discussion section of the paper, since how these 2 types of agents compare is 1 of the most common questions he has been getting about their results.

"We’re not suggesting, based on our study, that these melatonin-based therapies replace the hypnotics that are available," he said. "What we're suggesting is that tasimelteon is an effective treatment for circadian-rhythm sleep disorders, something that will target the underlying physiological complaint of the patient and improve the symptoms."

The study was funded by Vanda Pharmaceuticals. Dr. Rajaratnam has received grant support from Vanda, Takeda, the ResMed Foundation, and Phillips Lighting. Disclosures for other coauthors, including some who are employees of and stockholders in Vanda Pharmaceuticals, appear in the paper. Dr. Cardinali discloses that he has served as a consultant for Elisium. Dr. Golombek declares that he has no conflict of interest.

Lancet. Published online December 2, 2008.

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