ALLSCHWIL, Switzerland, Jan. 29, 2007 (PRIME NEWSWIRE) -- Actelion Ltd (SWX:ATLN) announced today the publication of both pre-clinical and placebo-controlled clinical data in the February edition of Nature Medicine1. These data demonstrate that Actelion's Orexin-OX1/OX2 receptor antagonist ACT-078573 induces characteristic signs of sleep in animal models as well as in man. In healthy human volunteers, signs of sleep -- such as reduced alertness -- were observed when ACT-078573 was administered during daytime, the active part of the circadian cycle in man.
Orexins are neuropeptides produced in the brain, or more specifically, by a very small number of dedicated neurons located in the hypothalamus2,3. Orexins play an important role in maintaining wakefulness and therefore regulate the sleep-wake cycle. ACT-078573 is the first oral orexin receptor antagonist that penetrates the blood-brain barrier and is capable of inducing a transient and reversible blockade of the two receptors, OX1 and OX2.
In animal models, the administration of ACT-078573 resulted in an increase in REM sleep. In contrast, the use of GABA-A receptor modulators such as zolpidem was associated with a decrease in REM sleep. REM stands for Rapid-Eye-Movement and describes the specific sleep phase where dreams occur. REM sleep is assumed to play a key role in the consolidation of different types of memory function.
Study findings in human
Within one hour after taking a single dose of 200mg (or higher) of the Orexin-OX1/OX2 receptor antagonist ACT-078573, healthy volunteers displayed signs of sleep. Treatment was well tolerated up to 1000mg with no severe or serious adverse events reported. Signs of sleep disappeared after six hours with a dose of 400mg.
These results were obtained in a randomized, placebo-controlled, double-blind, single-ascending dose Phase I study that enrolled 70 healthy male human subjects with no history of neurological, psychiatric or sleep disorders. They also had no history of drug or alcohol abuse.
Study participants were followed for up to twelve hours. During that period of time, they performed a variety of validated psychomotor performance tests, filled out a visual analog scale test used to assess alertness and questionnaires to rate sleep characteristics. In addition, EEG signals were recorded.
These healthy volunteers were randomized to receive either a single dose of ACT-078573 (n=6 for 7 different doses ranging from 1mg to 1000mg), placebo (n=14) or 10mg zolpidem (n=14, positive control group). In this study, healthy volunteers that received 10mg of zolpidem, a GABA-A receptor modulator approved for the treatment of insomnia, showed the expected signs of sleep. No signs of sleep were observed with placebo.
Clinical results confirmed earlier pre-clinical findings
The clinical study performed in healthy volunteers was initiated following a comprehensive pre-clinical program evaluating the pharmacological characteristics of ACT-078573. In these pre-clinical experiments, the species tested exhibited a dose-dependent decrease in alertness and increased Non-REM and REM sleep.
The current standard in insomnia treatment is to target the GABA-A receptor. Such GABA-A receptor modulators have demonstrated an increase in non-REM sleep, but a decrease in REM sleep.
In the pre-clinical and clinical studies discussed in Nature Medicine, there were no reports of cataplexy, a sudden loss of muscle tone, a frequent symptom of narcolepsy syndrome. A deficient orexinergic function is the hallmark of narcolepsy, a debilitating sleep disorder characterised by excessive daytime sleepiness. Additional pre-clinical and clinical studies are necessary to determine the full safety profile of this compound with a novel mechanism of action.
Potential of Orexin Receptor Antagonism in sleep disorders
Actelion is currently evaluating safety and efficacy of the OX1/OX2 receptor antagonist ACT-078573 in a Phase II program to assess the role of this compound in the treatment of sleep disorders.
Such evaluation is focusing not only on whether ACT-078573 induces and maintains sleep in insomnia patients, but will also attempt to demonstrate how antagonizing the orexin receptor could result in a different sleep and side effect profile compared to current sleep medications modulating the GABA-A receptor. Improvements may be possible in the areas of addiction, memory loss, muscular weakness and impaired next-day performance.
Special protocols are planned to assess REM sleep in humans and whether potential increases in REM sleep can positively affect memory function.
About ACT-078573
ACT-078573 is an Orexin-OX1/OX2 receptor antagonist. It was discovered by researchers at Actelion Pharmaceuticals in 2003. This compound is covered under a recently published patent application.
About sleep disorders
An International Classification of Sleep Disorders (ICSD) jointly developed by the American Academy of Sleep Medicine in association with the European, Japanese and Latin American Societies lists over 84 different types of sleep disorders. These 84 sleep disorders may be either temporary or chronic and they may be caused by a variety of physical, medical psychiatric or environmental factors.
In the United States alone, a 2005 National Institute of Health (NIH) State of Science conference about chronic insomnia estimated that there were up to 80 million Americans suffering from sleeplessness, of which 25 million suffered from chronic insomnia.
References:
1. Brisbare-Roch, C. et al. Promotion of sleep by targeting the
orexin system in rats, dogs and humans. Nature Medicine 2007
(currently accessible through Digital Object Identifier DOI
10.1038/nm1544 via http://dx.doi.org/
2. De Lecea, L. et al. The hypocretins: hypothalamus-specific
peptides with neuroexcitatory activity. Proc. Natl. Acad. Sci.
USA 95, 322-327 (1998).
3. Sakurai, T. et al. Orexins and orexin receptors: a family of
hypothalamic neuropeptides and G protein-coupled receptors that
regulate feeding behavior. Cell 92, 573-585 (1998).
Actelion Ltd
Actelion Ltd is a biopharmaceutical company with its corporate headquarters in Allschwil/Basel, Switzerland. Actelion's first drug Tracleer(r), an orally available dual endothelin receptor antagonist, has been approved as a therapy for pulmonary arterial hypertension. Actelion markets Tracleer(r) through its own subsidiaries in key markets worldwide, including the United States (based in South San Francisco), the European Union, Japan as well as Canada, Australia and Switzerland. Actelion, founded in late 1997, is a leading player in innovative science related to the endothelium -- the single layer of cells separating every blood vessel from the blood stream. Actelion focuses on the discovery, development and marketing of innovative drugs for significant unmet medical needs. Actelion shares are traded on the SWX Swiss Exchange (ticker symbol: ATLN).