New Data On Orexin Receptor Antagonist Almorexant Shows Therapeutic Potential To Restore Normal Physiological Sleep In Insomnia Patients
Actelion announced the results of its proof-of-concept/dose- ranging study1 into the effect of its first-in-class orexin receptor antagonist almorexant in 147 patients with primary insomnia. Due to be presented during the 2007 World Sleep Congress (WSC), Cairns, Australia, the results of this study prove that almorexant significantly improves 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 indicates that the use of almorexant results in clinically relevant improvements in important PSG-assessed sleep parameters. Almorexant was found - again in a dose-dependent fashion - to decrease Latency to Persistent Sleep (LPS, significant finding at 400 mg) and to decrease Wake After Sleep Onset (WASO, significant finding at 400 mg, 200 mg and 100 mg).
Almorexant - again in a dose-dependent manner - increased or maintained percentage of time spent REM (Rapid-Eye-Movement) sleep. 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).
Principal author Jasper Dingemanse, Ph.D. and Head of Clinical Pharmacology at Actelion commented: "These findings confirm the pivotal role of the highly specific orexin system in controlling the sleep-wake cycle. These data indicate that almorexant assists patients in falling and staying asleep in a non-sedative fashion, while at the same time not exhibiting any negative effects on next-day performance, as is commonly observed with traditional sleep medications targeting benzodiazepine receptors."
Jasper Dingemanse concluded: "Moreover, almorexant has demonstrated in this study its potential to restore to normal levels time spent in REM sleep. REM sleep is the phase in which we humans dream and this REM phase is thought to be of key importance for our ability to store and process information. Therefore, the orexin receptor antagonist almorexant has the unique potential to restore normal physiological sleep."
Isaac Kobrin, M.D. and Head of Clinical Development at Actelion said: "Based on these positive results, Actelion is planning to initiate by year-end the pivotal RESTORA program (REstore normal physiological Sleep with The Orexin Receptor antagonist Almorexant). The main doses to be evaluated in the adult population of patients suffering from insomnia will be 100 mg and 200 mg of almorexant taken before bedtime. The main parameters to be evaluated in this program include objective and subjective LPS and WASO as well as tolerability and safety."
Isaac Kobrin concluded: "Special emphasis will be put on profiling effects related to the unique mode of action of almorexant, such as positively affecting REM and non-REM sleep and improvement of next-day performance compared to medications targeting benzodiazepine receptors. In addition, the RESTORA program will include specific studies in elderly patients."
Jean-Paul Clozel, M.D. and Chief Executive Officer of Actelion, commented: "Our research efforts at Actelion have led to this highly innovative compound with the potential to transform how sleep disorders might be treated in the future. Actelion will support and drive the RESTORA program by putting behind it all required intellectual and material resources to fully characterize efficacy and safety of almorexant."
Safety and Tolerability data
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 published recently in Nature Medicine2. In all test settings, there have been no reports of cataplexy (sudden loss of muscle tone); a frequent symptom of narcolepsy syndrome associated with deficient orexinergic function.
Also presented during the World Sleep Congress 2007 is further data from the almorexant entry-into-human study in 70 healthy male subjects assessing tolerability, safety, pharmacokinetics and pharmacodynamics.3,4 Results revealed that the tested doses (1 up to 1000 mg) were well tolerated and there were no safety concerns. The pharmacokinetic and pharmacodynamic profile of almorexant is compatible with those required for an agent used in sleep disorders.
Actelion also disclosed at the WSC that an additional study performed in healthy volunteers receiving multiple-ascending doses (MAD) up to 1000 mg for up to six days showed comparable results to the single dose study. Detailed data from this MAD study is currently being prepared for later scientific presentation and publication.
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 under a recently published patent application. Actelion is now accelerating its efforts to advance this promising compound into the final stages of development, with the pivotal program RESTORA (REstore normal physiological Sleep with The Orexin Receptor antagonist Almorexant) expected to be initiated by year-end 2007.
The proof-of-concept/dose-ranging study design
This multicenter, multiple-stage, randomized, double-blind, placebo-controlled, single-dose, two-way crossover study recruited 161 men and women aged 18-65 years with primary insomnia (DSM-IV criteria) at 24 centers in Europe and Israel. The per-protocol population used in the efficacy analysis comprised 147 patients (39 at 400 mg, 38 at 200 mg, 38 at 100 mg and 32 at 50 mg of almorexant). Patients underwent a screening/adaptation night and two treatment nights (one night on placebo, one night on almorexant) separated by one-week intervals. Almorexant or placebo was administered 30 minutes before the start of polysomnography (PSG) recording and the time in bed was fixed to eight hours.
The primary objective of the proof-of-concept/dose ranging study was to demonstrate the efficacy of a dose of 400 mg of almorexant, thereafter assessing the efficacy of lower doses at 200 mg, 100 mg, and 50 mg. Secondary objectives, for which the study was not powered, included the effect of almorexant on LPS, WASO and tolerability.
The proof-of-concept/dose-ranging study results
The study achieved its primary endpoint demonstrating that almorexant significantly increased sleep efficiency in adult primary insomnia patients in a dose-dependent manner at 400 mg (p<0.001,) 200 mg (p<0.001) and 100 mg (p=0.019). Results for sleep efficiency at 50 mg did not reach statistical significance (p=0.119 ns), but were consistent with a dose-dependent response.
In terms of exploratory endpoints, almorexant decreased latency to persistent sleep (LPS) by up to 18.0 minutes and decreased wake after sleep onset (WASO) by up to 54.0 minutes. Latency to REM sleep was reduced by up to 45.2 minutes and subjective measures of total sleep time were increased by up to 55.1 minutes. The magnitude of treatment effect for each endpoint at each of the four doses suggests a dose-dependent response.
Almorexant had no effect on next-day performance in terms of a motor test and reaction time, suggesting an absence of 'hangover' often associated with sleep medications targeting the benzodiazepine receptors.
No safety concerns emerged during the conduct of the study.
The registration program RESTORA (REstore normal physiological Sleep with The Orexin Receptor antagonist Almorexant) will evaluate safety and efficacy of almorexant 100 mg and 200 mg in both adult and elderly patients diagnosed with insomnia. The RESTORA program will also include profiling studies, for example comparing almorexant with currently-used hypnotics targeting benzodiazepine receptors.
The RESTORA program, planned to be initiated by year-end 2007, is expected to last between two and three years. First study results could become available later in 2009.
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 USD 35 billion annually in the United States.
About REM sleep
REM is the stage of sleep during which most (though not all) dreams occur. During this stage, the eyes move rapidly behind the eyelids, and the activity of the brain's neurons is quite similar to that during waking hours. It is thought that memory is consolidated during REM sleep and is an important part of normal sleep architecture.
About Actelion Ltd
Actelion Ltd is a biopharmaceutical company with its corporate headquarters in Allschwil/Basel, Switzerland. Actelion's first drug TracleerÂ®, an orally available dual endothelin receptor antagonist, has been approved as a therapy for pulmonary arterial hypertension. Actelion markets TracleerÂ® 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).
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1. Dingemanse J et al. Proof-of-concept study in primary insomnia patients with almorexant (ACT-078573), a dual orexin receptor antagonist. Poster and oral presentation at the 5th World Congress of the World Federation of Sleep Research and Sleep Medicine Societies, Cairns, Australia, 2-6 September 2007; P0653-J.
2. 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.
3. Hoever P, et al. Entry-into-humans study with almorexant (ACT-078573), a dual orexin receptor antagonist: tolerability, safety and pharmacokinetics. Poster presentation at the 5th World Congress of the World Federation of Sleep Research and Sleep Medicine Societies, Cairns, Australia, 2-6 September 2007; PO444.
4. Hoever P, et al. Entry-into-humans study with almorexant (ACT-078573), a dual orexin receptor antagonist: pharmacodynamics. Poster presentation at the 5th World Congress of the World Federation of Sleep Research and Sleep Medicine Societies, Cairns, Australia, 2-6 September 2007; P0443.