Healthcare Industry News: TRACLEER
News Release - February 5, 2007
Successful Proof-of-Concept With Actelion's Orexin Receptor Antagonist in Patients Suffering From Primary Insomnia -- First Demonstration of Key Role of Orexin System in Humans Suffering From Sleep DisordersALLSCHWIL, Switzerland, Feb. 5, 2007 (Healthcare Sales & Marketing Network) -- Actelion Ltd (Swiss:ATLN.SW ) announced today that the proof-of-concept study in patients with primary insomnia receiving Actelion's Orexin-OX1/OX2 receptor antagonist ACT-078573 has met its primary endpoint, an improvement in sleep efficiency measured by Polysomnography (PSG).
This finding obtained in the per-protocol analysis from 39 patients receiving the starting dose in this multi-center, multiple-stage, double-blind, randomized, placebo-controlled, two-way crossover, single-dose study was highly statistically significant (p less than 0.0001).
Treatment was well tolerated and there were no reports of serious adverse events and no emerging safety findings. As the per-protocol criteria for study continuation have been met, the study now has moved to the next stage and continues with the dose-finding part to establish the lowest effective dose.
Isaac Kobrin, M.D. and Head of Clinical Development at Actelion commented: ``This finding exceeds our expectations. The magnitude of the observed effect clearly demonstrates that the orexin system plays a key role in insomnia patients. The study establishes in a highly significant way that when patients with primary insomnia received ACT-078573, they slept longer during the night compared to when they received placebo.''
Isaac Kobrin concluded: ``The magnitude of the effect on sleep efficiency -- time slept in a given period of time in which the patient is restricted to bed -- also suggests that all important aspects of sleep, such as sleep induction and sleep maintenance, may be positively affected by Actelion's Orexin-OX1/OX2 receptor antagonist ACT-078573.''
Phase III in chronic insomnia could be initiated by year-end 2007
After the ongoing study has identified the lowest effective dose, Actelion will analyze the trial in full detail and submit comprehensive results for publication in a peer-reviewed scientific journal of high standing.
Actelion is now accelerating its efforts to advance this promising compound into the final stages of development.
By the end of 2007, the company expects to generate all the information required to then start the large-scale pivotal Phase III program that evaluates safety and efficacy of Actelion's Orexin-OX1/OX2 receptor antagonist ACT-078573 as a treatment for patients suffering from chronic insomnia.
Such evaluation will not only focus 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.
Additional pre-clinical and clinical studies are also necessary to determine the full safety profile of this compound with a novel mechanism of action.
About the design of the combined proof-of-concept/dose-finding study
The ongoing combined proof-of-concept/dose-finding study is the first to test the effect of Actelion's Orexin-OX1/OX2 receptor antagonist ACT-078573 in patients suffering from primary insomnia, as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV).
The primary endpoint of this multi-center, multiple-stage, double-blind, randomized, placebo-controlled, two-way crossover, single-dose study is sleep efficiency measured by Polysomnography (PSG). PSG is an objective measurement of time spent in different stages of sleep (sleep architecture).
Secondary and exploratory endpoints include other objective and subjective measurements to assess sleep, especially latency to persistent sleep and waking after sleep onset. In addition, the study assesses the impact of receiving treatment with Actelion's Orexin-OX1/OX2 receptor antagonist ACT-078573 on next-day performance.
The study is currently ongoing, now testing safety and efficacy of lower doses.
Earlier findings published in Nature Medicine
The clinical results in patients suffering from primary insomnia add to the understanding of the role of the orexin system, as described in the February edition of Nature Medicine(1). This publication presents data generated by Actelion in both animal models and healthy human subjects.
In animal models, the administration of ACT-078573 resulted in an increase in REM sleep. In contrast, the use of the GABA-A receptor modulator zolpidem was associated with a decrease in REM sleep. REM stands for Rapid-Eye-Movement and describes the specific sleep phase in which dreams occur. REM sleep is assumed to play a key role in the consolidation of different types of memory function. Accordingly, special protocols in future clinical studies are planned to assess REM sleep in humans and whether potential increase in REM sleep period could positively affect memory function.
The Nature Medicine publication also reported the results of the first Phase I study. A randomized, placebo-controlled, double-blind, single-ascending dose Phase I study enrolled 70 healthy male human subjects. Volunteers receiving a single dose of 200mg (or higher) of the Orexin-OX1/OX2 receptor antagonist ACT-078573 displayed signs of sleep. Treatment was well tolerated up to 1000mg with no severe or serious adverse events reported. 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.
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. It was discovered by researchers at Actelion Pharmaceuticals in 2003. This compound is covered under a recently published patent application.
Orexins are neuropeptides produced in the brain, or more specifically, by a very small number of dedicated neurons located in the hypothalamus(2)(3). Orexins play an important role in maintaining wakefulness and therefore regulate the sleep-wake cycle.
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.
(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 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).
Actelion will host an Investor Conference Call and discussion/Q&A on Monday, February 5, 2007, 07.45 CET / 06.45 GMT / 01.45 a.m. EST
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Actelion webcasts its Investor Conference Call. On the Web, you may either follow the call live or have the call replayed later on demand.
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