RESET study demonstrates that tasimelteon maintains entrainment of melatonin and cortisol in totally blind individuals with non-24-hour circadian rhythms

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 130-162-Neuroendocrinology
Clinical
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-137
Steven W Lockley*1, Marlene A Dressman2, Changfu Xiao2, Louis Licamele2 and Mihael H Polymeropoulos2
1Brigham & Women's Hospital, Harvard Medical School, Boston, MA, 2Vanda Pharmaceuticals Inc., Washington, DC
Introduction: The majority of totally blind individuals exhibit non-24-hour circadian rhythms due to a lack of light signals reaching the brain, resulting in Non-24-Hour Sleep-Wake Disorder (Non-24), a serious circadian rhythm disorder with no FDA-approved treatment. Tasimelteon is a novel circadian regulator with selective agonist activity for melatonin MT1 and MT2 receptors that has previously been demonstrated in the SET study to entrain the circadian clock and improve sleep-wake measures.

Methods:  The RESET (Randomized-withdrawal study of the Efficacy and Safety of Tasimelteon to treat Non-24) is a multicenter, double-masked, placebo-controlled investigation of the maintenance effect of tasimelteon to treat Non-24 in totally blind patients. Patients were treated with 20mg open-label tasimelteon 1 hour before bedtime for 3 months. Patients who responded, defined as entrainment of their circadian clock to a 24 hour day (confirmed with urinary 6-sulfatoxymelatonin, aMT6s), were randomized to receive tasimelteon 20mg or placebo for 2 months. aMT6s and cortisol circadian periods were reassessed after randomization. Subjective nighttime sleep and daytime naps were reported daily throughout the study.

Results: 20 entrained totally blind patients (8F, age 28-70 yrs) were randomized to continue treatment or receive placebo. Tasimelteon-treated patients maintained entrainment of their circadian rhythms compared to placebo (aMT6s: 90% tasimelteon vs. 20% placebo p=0.0026; cortisol: 80% tasimelteon vs. 20% placebo p=0.0118). Total nighttime sleep in the worst quartile of nights was 67.2 minutes longer and total daytime sleep duration was 59.4 minutes shorter in tasimelteon-treated patients (p< 0.05). The midpoint of sleep timing from both nighttime and daytime sleep increased 36 minutes in tasimelteon treated patients (p=0.0108). Tasimelteon was safe and well-tolerated.

Conclusion:  Tasimelteon entrained circadian rhythms as measured by melatonin and cortisol in totally blind patients with Non-24. Discontinuation of tasimelteon resulted in loss of entrainment which was correlated with an approximate 60 minute decrease in nighttime sleep and an equivalent increase in daytime napping. The RESET study demonstrates the necessity for chronic treatment with tasimelteon in Non-24.

Disclosure: SWL: Investigator, Vanda Pharmaceuticals Inc. . MAD: Employee, Vanda Pharmaceuticals Inc. . CX: Employee, Vanda Pharmaceuticals Inc. . LL: Employee, Vanda Pharmaceuticals Inc. . MHP: , Vanda Pharmaceuticals Inc. .

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Vanda Pharmaceuticals Inc. (ClinicalTrials.gov NCT01430754)