ALLSCHWIL, Switzerland, Dec. 20, 2007 (PRIME NEWSWIRE) -- Actelion Ltd (SWX:ATLN) announced today that the company has initiated the comprehensive Phase III program RESTORA (REstore physiological Sleep with The Orexin Receptor Antagonist Almorexant) with its first-in-class orexin receptor antagonist, almorexant.
The first Phase III study, RESTORA 1, is a multi-center, double-blind, randomized, placebo-controlled, active reference, parallel-group polysomnography study to evaluate efficacy and safety of almorexant in approximately 670 patients diagnosed with primary insomnia. Enrolment will take place in 70 clinical study centers in Asia, Australia, Europe, Israel and Latin America. A list of enrolling centers is being posted on www.clinicaltrials.gov.
RESTORA 1 is expected to confirm the effects of almorexant on sleep induction and sleep maintenance that were previously observed. This study is also expected to provide additional information on sleep architecture and sleep quality, thereby providing further insight into the role of almorexant in restoring normal physiological sleep.
RESTORA 1 also includes an active reference arm with zolpidem to generate reference information with this agent approved for the treatment of insomnia. Study results should become available in 2009.
In 2008, Actelion will initiate additional placebo-controlled Phase III studies, expanding into North America and focusing on longer treatment exposure, additional exploratory endpoints and different populations such as elderly patients (65 years of age or older). To define the optimal dose range to be used in the elderly, Actelion is currently enrolling geriatric patients into a dose-finding study conducted in the United States under an IND (Investigational New Drug Application) with the US Food and Drug Administration.
The results of these Phase III studies plus other completed and ongoing studies are expected to form the basis for regulatory submissions throughout the world.
Goran Hajak, M.D. and Professor of Psychiatry at the University of Regensburg (Germany) and member of the RESTORA Steering Committee, commented: "The RESTORA program -- expected to enroll several thousand patients over the coming two to three years -- will provide us with detailed safety and efficacy information on the potential use of almorexant as an insomnia treatment. Earlier studies suggest that almorexant may be an effective agent, potentially without the side effects associated with currently available sleep agents that target the benzodiazepine receptor. With RESTORA 1, we have the opportunity to gain additional insight into the different modes of action of either class."
Jean-Paul Clozel, M.D. and Chief Executive Officer of Actelion, added: "Actelion is committed to fully evaluate the potential role of almorexant in insomnia and beyond. Given its novel mode of action and the substantial body of pre-clinical and clinical data available today, I strongly believe that almorexant has the potential to transform our approach to treating sleep disorders. In addition, success with almorexant should significantly accelerate Actelion's future growth."
In order to maximize the full transformational potential of almorexant, Actelion has recently initiated a partnering process to evaluate major pharmaceutical companies in order to select the optimal commercial partner.
About RESTORA 1
The RESTORA 1 study is a multi-center, double-blind, randomized, placebo-controlled, active reference, parallel-group polysomnography study to confirm the efficacy and safety of almorexant in adult subjects with chronic primary insomnia. The study will enroll at approximately 670 patients from approximately 70 centers in countries from Asia, Australia, Europe, Israel and Latin America. Patients will be randomized 1:1:1:1 to two doses of almorexant (100 mg and 200 mg), placebo and zolpidem (10 mg) as an active reference.
The study is designed to demonstrate the effect of almorexant versus placebo on sleep onset (Latency to Persistent Sleep - LPS) and/or sleep maintenance (Wake-after-sleep onset - WASO) as determined by polysomnography. Secondary objectives of the study include evaluation of almorexant versus placebo on subjective parameters - self reported time to fall asleep (sLPS) and self reported wake time during sleep (sWASO) -- as well as safety and tolerability. The study will also provide information about the potential benefits of almorexant on sleep architecture and the potential of this novel agent to restore normal physiological sleep.
Previous studies supporting RESTORA
Prior to initiation of the RESTORA study, a proof-of-concept/dose-ranging study in patients with primary insomnia indicated that almorexant significantly improved the primary parameter of sleep efficiency (time spent sleeping while confined to bed during an eight hour period at night) measured by polysomnography (PSG) -- at 400 mg, 200 mg and 100 mg in a dose-dependent manner.
Analysis of secondary and exploratory endpoints, for which the study was not powered, also indicated that the use of almorexant resulted in other clinically relevant improvements in important PSG-assessed sleep parameters. Almorexant was found -- in a dose-dependent fashion -- to decrease LPS, (significant finding at 400 mg) and to decrease WASO, (significant finding at 400 mg, 200 mg and 100 mg).
Almorexant increased or maintained both percentage of time spent in REM (Rapid-Eye-Movement) and non-REM sleep in a normal proportion. Almorexant also significantly improved subjective sleep variables. Treatment with almorexant was not associated with any relevant negative effects on next-day performance (assessed by fine motor testing and mean reaction time).
Treatment with almorexant was well tolerated and there were no reports of serious adverse events and no emerging safety findings. These results are consistent with earlier observations made in pre-clinical and early clinical studies recently published in Nature Medicine (1).
The entry-into-human study in 70 healthy male subjects assessing tolerability, safety, pharmacokinetics and pharmacodynamics revealed that the tested doses (up to 1000 mg) were well tolerated and there were no safety concerns. A multiple-ascending dose (MAD) study performed in both female and male healthy subjects receiving up to 1000mg for up to six days showed similar results.
Notes to editors
About almorexant
Almorexant is the first-in-class orexin receptor antagonist in clinical development as a potential new treatment for insomnia. It is an oral therapy that penetrates the blood-brain barrier and is capable of inducing a transient and reversible blockade of the orexin receptors. It was discovered by researchers at Actelion Pharmaceuticals in 2003. Almorexant is covered by a patent application.
About RESTORA
The registration program RESTORA (REstore normal physiological Sleep with The Orexin Receptor antagonist Almorexant) will evaluate efficacy and safety of almorexant in both adult and elderly patients diagnosed with insomnia. The RESTORA program also includes profiling studies, for example comparing almorexant with currently used hypnotics targeting benzodiazepine receptors.
The RESTORA program is expected to last between two and three years, with initial Phase III results expected in the second half of 2009. Additional supportive study results (for example long-term exposure in healthy volunteers, drug-drug interaction etc) will become available starting in 2008.
About orexins
Orexins are proteins produced by the hypothalamus. They play an important role in controlling the sleep-wake cycle.
About sleep disorders
In the United States alone, a 2005 National Institutes 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. Insomnia has a significant health and quality-of-life impact. People with insomnia tend to have higher rates of mental health problems, drug and alcohol abuse, and cardiac morbidity. The direct and indirect economic costs of sleep disorders are estimated to be up to USD35 billion annually in the United States.
References
1. Brisbare-Roch C. et al. Promotion of sleep by targeting the orexin system in rats, dogs and humans. Nat Med. 2007 Feb;13(2):150-5.
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, Canada, Australia and Switzerland. At the end of September 2007, Tracleer(r) was commercially available in 35 countries worldwide. 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's over 1,500 employees focus 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).