Therapy Analysis - Sleep, A Mental Mystery
Pharmcological intervention
Although the last decade has seen a steady increase in the number of drugs in development for sleep disorders, there are still relatively few drugs approved or launched in the field of sleep disorders. As of January 2009, Pharmaprojects' data indicates just 12 drugs registered or launched, with 43 potential drugs still negotiating the ever-precarious landscape of preclinical and clinical testing, and a further 8 awaiting approval (Graph 1). In pharmacological terms, nonbenzodiazepine hypnotics, dopamine D2 antagonists and orexin antagonists seem to be emerging as the front-runners in the treatment of sleep disorders (Graph 2).
Amongst the more well-known and long-established treatments for narcolepsy is Cephalon's modafinil, a psychostimulant first launched in France in 1994 as Modiodal for the treatment of hypersomnia and Gelineau's syndrome. It has since been launched in numerous world markets for the treatment of narcolepsy. In previous Phase III trials, modafinil increased wakefulness and daytime alertness scores. In a US Phase III trial in 273 narcolepsy patients, once-daily treatment with modafinil for 9 weeks increased wakefulness by up to 50% compared to placebo. A slightly more recent addition is Jazz Pharmaceuticals' dopaminergic antagonist, sodium oxybate (Xyrem), which was first launched in the US in 2002. This drug undergoes metabolism to gamma hydroxybutyrate (GHB), thereby inhibiting presynaptic dopamine release. It is now launched in several markets for the treatment of narcolepsy-related cataplexy. In a previous Phase III trial in narcolepsy patients, sodium oxybate at doses of 4.5-9g reduced inadvertent daytime naps and night-time awakenings, and was effective in reducing cataplectic attacks at all doses tested. Xybrem is currently licensed to UCB and Valeant Pharmaceuticals for Europe and Canada, respectively.
Another Cephalon compound showing future promise is armodafinil, the R-isomeric form of modafinil, which boasts an extended duration of action. In Phase III trials in Australia, Canada, Europe and the US in 300 patients, armodafinil 150mg and 250mg per day met all primary endpoints of objective sleep latency and was generally well tolerated. Armodafinil is currently approved in the US for the treatment of excessive daytime sleepiness associated with narcolepsy, sleep apnoea and shift work sleep disorder, with launch expected in the second half of 2009.
Ramelteon is a melatonin receptor antagonist, developed by Takeda for the treatment of insomnia, sleep apnoea and other sleep disorders. It is launched in the US as Rozerem for the treatment of insomnia, and is awaiting approval in Japan. An EU MAA for the treatment of insomnia was withdrawn following a negative opinion from the EU CHMP. In a Phase III trial in elderly patients with chronic insomnia, ramelteon reduced time to falling asleep, with no rebound insomnia or withdrawal observed. In a Phase II trial in sleep apnoea patients, ramelteon increased oxygen saturation in REM sleep compared to placebo. It is also in a Phase II trial for circadian rhythm sleep disorders.
Treatment for RLS currently involves GlaxoSmithKline's oral dopamine D2 receptor agonist ropinirole, currently launched in several world markets for the treatment of this condition. In a US randomized Phase III trial in 380 patients with idiopathic RLS, ropinirole significantly improved IRLS scores compared to placebo, while improving measurements of subjective sleep disturbance, sleep quality and daytime somnolence. It is also launched for the treatment of Parkinson's disease, highlighting the similarities in pathology underlying these conditions.
