Safety profile of tasimelteon, a melatonin MT₁ and MT₂ receptor agonist: pooled safety analyses from six clinical studies

Abstract

Introduction: Tasimelteon, a novel circadian regulator, is the first product for the treatment of Non-24-hour Sleep-Wake Disorder (Non-24) approved by either the FDA or the European Medicines Agency (EMA). Tasimelteon is a potent and specific melatonin (MT₁ and MT₂) receptor agonist with 2 – 4 times greater affinity for the MT₂ receptor.

Methods: Safety was assessed in two controlled and two open-label studies in blind individuals with Non-24 and in two controlled studies of primary insomnia. Periodic assessments included collection of adverse events (AEs), laboratory testing, electrocardiograms (ECGs), vital sign monitoring, physical examinations and assessment for the potential for suicide. One study included additional assessments for endocrine function.

Results: A total of 184 blind individuals with Non-24 received tasimelteon nightly with a median exposure > 1 year. In placebo-controlled studies, 387 patients with insomnia and 42 patients with Non-24 received tasimelteon nightly for 4 – 26 weeks. The total patient years exposure for the six studies assessed here is 258.64 patient years. Discontinuations due to AEs were similar across treatment groups. Overall in the clinical studies described here, AEs attributable to tasimelteon treatment were headache, diarrhea, dry mouth, alanine aminotransferase increased, somnolence, dizziness and nightmare/abnormal dreams. There were no clinically significant differences in treatment group with ECGs, vital signs, withdrawal, endocrine function and suicidality assessments.

Conclusion: Long-term tasimelteon administration was safe and well-tolerated. This is supported by placebo-controlled data in both Non-24 and insomnia patients.

Keywords:

• blindness
• circadian
• melatonin receptor agonist
• non-24-h sleep-wake disorder
• safety
• tasimelteon

Acknowledgments

The authors thank the volunteers, without whom the project could not be conducted, and organizations for the blind and visually impaired for their support in developing and promoting the study (full list available in Supplemental Materials). We are indebted to the investigators and staff of the study sites, whose role was also vitally important. The Site Principal Investigators were (in alphabetical order, * denotes investigators participating in multiple studies): Drs. Rosanne Armitage, Bijan Bastini, Michael Biber, Jed Black, Joe Blumenau, Richard Bogan*, James Borders, Michael Borneman, Valierie Cochen De Cock, Martin Cohn, Bruce Corser, Craig Curtis, Yves Dauvilliers, Eugene DuBoff, Ilonka Eisensehr, Helene Emsellem*, Milton Erman*, Thierry Faivre, Alan Feiger, Ingo Feitze, Neil Feldman*, James Ferguson, Jonathan Flescher, Steven Folkerth, June Fry*, Yury Furman, Mandeep Garewal, J. Christian Gillin, Mark Gotfried*, Gina Graci, Daniel Grosz, Paul Haberman, Robert Hart*, Jörg Heitmann, John Hudson, Steven Hull, Keith Ironside, Steven James, Andrew Jamieson, Fabrice Laine, P. David Laman, Jr.*, D. Alan Lankford*, Kurt Lesh, Steven Lockley*, Peter Londborg, Daniel Lorch Jr.*, Mark Mahowald, Irmgard Marten, David Mayleben, Deborah Metzger, Denis Munjack, Daniel Norman*, William Orr*, Allan Pack, G. Vernon Pegram, Richard Pellegrino, Michel Phillppe, Isabelle Poirot, Kathleen Rice, Veronika Richter, Dennis Riff, Daniel Rifkin, Russell Rosenberg, Murray Rosenthal*, Thomas Roth, Beth Safirstein, R. Bart Sangal, Francine Santoro, Martin Scharf*, Howard Schwartz*, Markus Schmidt*, Andrew Schreiber*, Paula Schweitzer*, David Seiden, William Seiple*, Clifford Singer, Robert Sotolongo, Egilius Spierings, Brock Summers, Todd Swick*, Malgorzata Szyfer, Stephen Thein, Michel Tiberge, Mark Viner, Gerald Vogel, James Walsh*, Joerg Walther, J. Catesby Ware, James Weintraub*, David Winslow, Paul Wylie, Gary Zammit, and Jamie Zeitzer* as well as statistical support and medical review from Changfu Xiao, Mark Forsberg, Paolo Baroldi, and Kyong Park.

Declaration of interest

D Leger has received funding or has been the main investigator in studies sponsored by SANOFI-AVENTIS, MERCK, VANDA, ACTELION, BIOPROJET, PHILIPS, RESMED, VITALAIRE in the last 5 years. He has been principal investigator in the 3202 study and he received fees and compensation for performing these surveys. He declares having access to all safety reports and documents made during the survey. MF Vecchierini has been the main investigator in a study sponsored by RESMED and a co-investigator in studies sponsored by VANDA, MERCK and BIOPROJET. She has been a co-investigator in the 3202 study and has received fees for this study. P Ogrizek received fees for being a co-investigator in the 3202 study sponsored by VANDA and has been invited by UCB and VITALAIRE to attend international congresses in the last 5 years. M-A Quera-Salva has received funding or has been the main investigator in studies sponsored by SERVIER, VANDA, ACTELION, BIOPROJET, PHILIPS, ASSOCIATION Française contre les Myopathies, Les Gueules casés, Fondation Vinci pour une conduite responsible. Has received consulting fees from servier and vanda. C Perry and MA Dressman are employees of Vanda Pharmaceuticals. The research reported in this manuscript was funded by Vanda Pharmaceuticals and Bristol Myers Squibb. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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