About almorexant in clinical development
Almorexant is a first-in-class orexin receptor antagonist which has the potential to shift the paradigm for treating sleep disorders. 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. Orexins are neuropeptides produced in the brain, or more specifically, by a very small number of specialized neurons located in the hypothalamus. Orexins play an important role in maintaining wakefulness, and therefore regulate the sleep-wake-cycle. Almorexant was discovered in an in-house research program.
Current status
Actelion and GSK entered into an exclusive worldwide (excluding Japan) collaboration in July 2008 to jointly develop and commercialize Actelion’s first-in-class orexin receptor antagonist almorexant.
Almorexant is currently investigated in the comprehensive Phase III program RESTORA (REstore physiological Sleep with The Orexin Receptor antagonist Almorexant). The first Phase III study, RESTORA 1, commenced enrollment in the second quarter of 2008 and is designed to evaluate efficacy and safety of almorexant in patients diagnosed with primary insomnia.
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 includes an active reference arm with zolpidem to generate reference information with this agent approved for the treatment of insomnia.
As of October 2008 the Actelion/GSK collaboration on almorexant was fully operational and the two companies expect to initiate in the coming months further clinical studies as part of the Phase III program. This follows End-of-Phase II discussions with the US Food and Drug Administration (FDA). During these discussions, Actelion provided the FDA with additional four-week safety data generated in healthy volunteers as well as with results from a successful dose-finding study with almorexant in elderly patients.
Available clinical data
A proof-of-concept/dose-ranging study in patients with primary insomnia indicated that almorexant significantly improved the primary parameter of sleep efficiency, as measured by polysomnography (PSG), 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 to decrease latency to persistent sleep (LPS) and wake-after-sleep onset (WASO), again in a dose-dependent manner.
Almorexant increased or maintained the percentage of time spent in both 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. There were no reports of serious adverse events, and no emerging safety findings. These results are consistent with earlier observations made in preclinical and early clinical studies published in Nature Medicine.
The entry-into-humans study in 70 healthy male subjects assessing tolerability, safety, pharmacokinetics and pharmacodynamics revealed that the tested doses (up to 1,000 mg) were well tolerated, and there were no safety concerns. A multiple-ascending dose study, performed in healthy female and male volunteers receiving up to 1,000mg for up to 6 days, showed similar results.
Milestones
2008 – Exclusive world-wide (excluding Japan) collaboration entered into with GlaxoSmithKline
2007 – Phase III RESTORA study initiated
2005 – Entry-into-man study initiated
1998 – Project initiated in-house in 1998
Key scientific literature
Hoever P, et al. Multiple-dose pharmacokinetics, pharmacodynamics, safety and tolerability of the orexin receptor antagonist almorexant in healthy subjects. Poster presentation at SLEEP 2008 22nd Annual Meeting of the Associated Professional Sleep Societies, LLC (APSS) June 7-12, 2008
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.
Brisbare-Roch C. et al. Promotion of sleep by targeting the orexin system in rats, dogs and humans. Nat Med. 13(2):150-5; 2007.
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.
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.
