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In the midnight hours

Companies have woken up to the market potential of long-term treatments for insomnia

In the industrialised world, insomnia affects 5 to 10 per cent of adults, with the incidence rising to a massive 25 per cent in the elderly. It is categorised as primary or secondary: primary insomnia is caused by a psychophysiological hyper-arousal process, while secondary insomnia, which affects 80 per cent of people with the disorder, is classed as secondary to another medical or psychiatric illness, and is often linked to depression, pain and breathing problems.

Insomnia has a high socio-economic burden, as it is associated with increased absenteeism, reduced work performance and an increased risk of accidents. Inadequate sleep has long-term health consequences and is also linked to increased use of healthcare resources, including higher rates of hospitalisation. Unfortunately, insomnia often goes untreated, as the majority of patients do not discuss sleep problems with their doctor. Those that do, however, have a growing number of therapeutic options available to them.

Traditional methods
Traditionally, the standard of care for patients with insomnia has been short-term use of benzodiazepine hypnotics, which are benzodiazepine receptor agonists that depress the central nervous system. These drugs, such as estazolam, flurazepam, quazempam and temazepam, reliably induce sleep and have the pharmacokinetic profile to maintain therapeutic effect through the night. However, such drugs are associated with undesirable side effects including dependency, and counter-therapeutic next-day effects, such as drowsiness and impaired cognitive function. Tolerance to benzodiazepines is also common. The first group of so-called non-benzodiazepine hypnotics approved for use in patients with insomnia are structurally different from benzodiazepines but also act as benzodiazepine GABA receptor agonists. This group includes drugs such as zolpidem, zaleplon and zopiclone. The majority of these drugs are approved for short-term use and are most effective in treating patients with sleep-initiation insomnia. GABA receptor agonists have a shorter half life than benzodiazepines and are less likely to produce residual, next-day effects.

It was not until the launch of zolpidem extended release (XR) and eszopiclone in 2005 that an effective medication was available for the long-term treatment of both sleep-initiation and sleep-maintenance insomnia. Zolpidem XR, marketed as Ambien CR by sanofi-aventis, acts rapidly without major alteration of the electrophysiological sleep architecture and with no subjective or objective next-day effects. The extended release formulation of zolpidem has linear kinetics and allows the serum concentration to be maintained throughout the night but to decrease by the time the patient awakes for the day. Zolpidem XR is vying for market share with Sepracor's eszopiclone (Lunesta) in the US. Eszopiclone was the first non-benzodiazepine to be approved for the treatment of sleep- maintenance insomnia for an unlimited length of time. Zolpidem XR releases the drug over time to maintain sleep, whereas a higher bedtime dose of eszopiclone is required to gain the same effect. Higher doses of eszopiclone are associated with a higher frequency of adverse events. As yet, no head-to-head trials between zolpidem XR and eszopiclone have been conducted. It seems that while sanofi-aventis and Sepracor were the first companies to gain approval for drugs for the long-term treatment of sleep-maintenance insomnia, several others have realised the potential of this market. Wyeth has followed the lead of sanofi-aventis and is developing a modified release formulation of zaleplon, an established non-benzodiazepine hypnotic, which is currently in phase II development in the US.

In development
Neurocrine Biosciences is developing both immediate and controlled-release formulations of indiplon, also a benzo-diazepine GABA receptor agonist, for insomnia. The immediate release formulation decreased time to sleep onset in phase III trials and was approved by the US Food and Drug Administration (FDA) in May 2006 for use in sleep-initiation and middle-of-the-night dosing. However, the FDA refused to approve the modified release formulation for sleep maintenance. Neurocrine was seeking approval for indiplon 15mg despite the fact that in clinical trials the company used indiplon 20-30mg which showed good efficacy in maintaining sleep. Another benzodiazepine GABA receptor agonist, gaboxadol, is in development with Lundbeck for the treatment of primary insomnia. In phase II trials, gaboxadol enhanced slow wave sleep and increased total sleep time. Lundbeck is conducting trials in North America and Europe, and hopes to file for regulatory approval in the US in mid-2007. Eplivanserin (sanofi-aventis) is an orally active, selective antagonist of the serotonin2 receptor. It is currently in phase III trials for the treatment of sleep-maintenance insomnia worldwide and was well-tolerated with no next-day effects or rebound insomnia in phase II studies. Melatonin receptor agonists, such as Takeda's ramelteon (Rozerem) have also proven effective in treating insomnia. Vanda Pharmaceuticals is currently developing VEC 162, an oral melatonin receptor agonist, which has performed well in phase II and III trials in volunteers with phase-advance, transient insomnia

11th May 2007


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