London Friday May 18 2007- Sleep is essential for both mental and physical restoration and accounts for about one third of our lives. While many of us occasionally experience a night or two of tossing and turning, for sufferers of insomnia, continued lack of sufficient sleep can have a substantial impact on daytime functioning and quality of life. Estimated to be worth $6.1 billion in 2006**, according to a new report* from the independent market analyst Datamonitor (DTM.L), the insomnia market is set to grow to $7.7 billion by 2016**, driven by the continued uptake of existing brands such as Sanofi-Aventis’s Ambien CR (controlled release) and the entrance of a new drug class, the serotonin antagonists which represent the most significant improvement on currently available treatments in some years.

Insomnia is under-diagnosed and carries a high socioeconomic impact

Insomnia is the most pervasive of the sleep disorders, with approximately 29 million diagnosed sufferers across the seven major markets, and is characterized by difficulty initiating sleep, difficulty maintaining sleep or waking up unrefreshed. For sufferers, this may lead to various symptoms including fatigue, mood disturbance, confusion, or irritability as well as leading to an increased risk of accidents. Despite the high prevalence of insomnia symptoms in the general population, approximately only six percent receives a diagnosis from a physician, with the majority either ignoring the problem or using self-help methods such as alcohol, natural remedies or over-the-counter (OTC) products.

Inadequate identification and treatment of insomnia is associated with increased risk of medical and psychiatric disorders, leading to increased healthcare costs, and also has a detrimental effect on companies’ workforces in terms of absenteeism. According to a survey by the National Sleep Foundation, 46% of individuals with frequent sleep disturbances report missing work or events or making errors at work, compared to 15% of healthy sleepers, says Datamonitor central nervous system (CNS) analyst Charlotte Mackey. "The ideal insomnia medication not only needs to induce sleep quickly, and maintain sleep, but also be suitable for elderly patients and not carry the risk of tolerance and addiction."

Indiplon’s delayed approval continues as FDA requests additional safety information

The insomnia market is currently dominated by GABAa receptor modulator class of drugs, chiefly Sanofi-Aventis’s Ambien (zolpidem). The ongoing approval delays with Neurocrine’s indiplon and the recent discontinuation of Merck and Lundbeck’s gaboxadol is testimony to the high level of competition within this drug class, Mackey says.

Neurocrine’s indiplon has required the most extensive submission package for an insomnia treatment to date and its fate remains in the hands of the FDA. The drug represents the company’s first insomnia product and is being developed as two separate formulations: modified-release (MR) and immediate-release (IR).

In May 2006, Neurocrine received a non-approvable letter from the FDA for the MR formulation and by November the agency had also requested additional long-term safety and efficacy data for the adult dose and the development of a separate formulation for elderly patients. Neurocrine plans to resubmit the new drug application (NDA) for indiplon MR at the end of the second quarter of 2007. Owing to the FDA’s request for further analysis of trial data, the company also plans to resubmit the NDA for indiplon IR at this time. However, opinion leaders interviewed by Datamonitor regard indiplon as a ‘me-too’ drug that does not confer any substantial advantage over currently marketed hypnotics, Mackey says. "Furthermore, in view of Pfizer’s termination of its co-development agreement with Neurocrine in June 2006, Datamonitor believes that Neurocrine will struggle to find a co-development partner for the drug, a factor which will severely limit penetration if it eventually reaches the market."

Failure of gaboxadol is good news for competition

In late March 2007, Merck & Co. and Lundbeck announced the discontinuation of their Phase III drug, gaboxadol, due to disappointing Phase III trial results. While earlier trials had demonstrated the drug’s effectiveness in sleep onset and maintenance, such positive efficacy results failed to be replicated in subsequent trials. In addition, gaboxadol was found to cause concerning side effects including hallucinations, dizziness and vomiting at doses as low as twice the recommended dose, Mackey says. "Since the combined marketing presence of Merck and Lundbeck would have conferred a substantial commercial advantage to gaboxadol, the elimination of the drug from the pipeline drastically reduces competition for remaining marketed and pipeline drugs."

Eplivanserin represents Sanofi-Aventis’s franchise extension

The delayed approval of indiplon and discontinuation of gaboxadol is indicative of the high level of competition within the GABAa class of drugs. With eight identified products in development, the serotonin antagonists have now become the most prevalent drug class in the late stage insomnia pipeline, indicating a move away from the present dominance of the GABAa class in the market. Datamonitor believes that serotonin antagonists are set to be important players in the insomnia market in the future, because it is the drug class which is closest to achieving an improvement in sleep maintenance, and reducing next-day residual sedation, while possessing a novel mechanism of action. Furthermore, serotonin antagonists are unlikely to be classified as a controlled substance by the US Drug Enforcement Agency (DEA), meaning that the drugs carry no potential for tolerance and addiction.

"The fact that the current market leader, Sanofi-Aventis, has two serotonin antagonists in late stage development is indicative of the company’s high level of confidence in this drug class as a treatment for insomnia," Mackey says.

With 13 generic manufacturers given the go-ahead by the FDA to launch generic zolpidem at the time of writing, these two pipeline drugs represent an additional effort to the launch of Ambien CR in 2005 to maintain Sanofi-Aventis’s leader status in the insomnia market. In 2006, the company’s Ambien franchise occupied 62% of the branded insomnia market, Mackey says. "Eplivanserin, which is presently in Phase III development, is expected to be the first serotonin pipeline drug to reach the market and as such will benefit from ‘novel drug’ status.

"Sanofi-Aventis’ strong presence in the insomnia market and existing relationship with prescribing physicians bodes well for the launch of eplivanserin. Datamonitor believes eplivanserin will become a major player in the insomnia market, with sales forecast to reach $913m by 2016," she says.

Notes

* Pipeline Insight: Insomnia – Targeting the sleep maintenance market

**seven major markets: UK, US, France, Germany, Italy, Japan and Spain, MIDAS Sales Data, IMS Health, March 2007

Datamonitor’s report Pipeline Insight: Insomnia – Targeting the sleep maintenance market, provides analysis of drugs in late-stage clinical development for use in insomnia, including important clinical trial results, patient potential, market potential, and forecasts to 2016; supported by key opinion leader comments.