Therapy Analysis - Sleep, A Mental Mystery
Future therapies
Moving forward and looking at novel pharmacologies as yet untested in sleep disorders, the histamine-3 receptor is under investigation as a possible target for treatment of narcolepsy. GlaxoSmithKline's 189254, which was originally in development for Alzheimer's disease, showed high affinity for H3 receptors in the cerebral cortex, and produced dosedependent increases in levels of acetylcholine, dopamine and noradrenaline. This compound is currently undergoing Phase II trials in narcolepsy, whilst Johnson & Johnson's JNJ- 28583867, which showed in vivo activity at H3 receptors, and increased extracortical levels of 5-HT, dopamine and noradrenaline, is currently under preclinical investigation for the treatment of cognitive disorders.
Almorexant is an orexin receptor antagonist, under development by Actelion for the treatment of insomnia. It is currently in a Phase III trial in 670 primary insomnia patients to assess efficacy of 100mg and 200mg oral doses, as well as safety and tolerability. Results are expected in 2009. It has also shown positive results in a Phase II trial in 39 insomnia patients, where it demonstrated a significant improvement in sleep efficiency, with no adverse events or safety concerns. GSK has co-development and commercialization rights (excluding Japan) to almorexant, with Actelion to receive upfront and milestone payments.
Jazz Pharmaceuticals is developing JZP-7, a transdermal formulation of ropinirole for the treatment of RLS. It is licensed to Antares Pharma, utilising its ATD delivery technology, and is currently in Phase II trials. In Phase I pharmacokinetic studies, JZP-7 was safe and well tolerated, and achieved dose-escalation to higher doses. Phase III trials are expected in 2009, with an NDA filing and subsequent launch planned for 2011 and 2012, respectively.
An early-stage compound in the treatment of sleep apnoea is PPI-03306, under development by Biovail (Prestwick Pharmaceuticals before the acquisition). It modulates an enzyme involved in the synthesis of 5-HT. Biovail has exclusive development and commercialization rights to PPI- 03306 for the treatment of sleep apnoea and other conditions.
After more than 50 years of research, initiated by the pioneering work of Drs. Nathaniel Kleitman and Eugene Aserinsky, who in 1953 discovered REM during sleep, still relatively little is known or understood about the physiological function and importance of sleep. Sleep research has, and still does, suffer from an inability to create suitable models to base research on, as the sleeping behaviours of other mammals are quite different from that of humans.
Modern sleep research is highly diverse and covers many different and overlapping topics, such as circadian neurobiology, sleep and pain, cancer and sleep disorders to name but a few. Hopefully these new efforts may yield answers to an array of perplexing questions regarding the physiology, evolution, control and need for sleep These answers could help to improve diagnosis, management and treatment of sleep disorders, and could help to improve our general well being, sleep behaviour and mental health. As the conscious efforts of those in the field of sleep research and drug development continue, the near future may indeed uncover these mysteries of the unconscious.
Naila Shaw
Pharmaprojects Analyst
