Future developments
Almorexant
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 by Actelion scientists in an in-house research program.
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.
Current Status
Almorexant is currently being investigated in the comprehensive Phase III program RESTORA (REstore physiological Sleep with The Orexin Receptor antagonist Almorexant). The first Phase III study, RESTORA 1 has commenced enrollment and is designed to evaluate the 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 have previously been 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. The 700-patient study RESTORA 1 includes a reference arm with zolpidem, an approved treatment for insomnia. Study results are expected in Q4 2009.
The Actelion/GSK collaboration is currently investing time in finalizing the design for the remaining almorexant RESTORA program to gain a Special Protocol Assessment (SPA) from the FDA. The collaboration now expects to resubmit the clinical protocols to the FDA by the end of the year. Accordingly, these pivotal studies are expected to be initiated no sooner than early 2010. In the meantime the non-pivotal program is ongoing.
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 (the time asleep during the night divided by the time spent in bed), 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 almorexant elicited improvement in other clinically important PSG-assessed sleep parameters. Almorexant was found to decrease latency to persistent sleep (LPS – the time it takes to go to sleep) and wake-after-sleep onset (WASO – the amount of time spent awake after initial sleep onset), again in a dose-dependent manner.
Almorexant increased the time spent in both REM (Rapid-Eye-Movement) and non-REM sleep to levels similar to normal sleepers. Almorexant also significantly improved patient-reported 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, the results of which have been published in Nature Medicine.
The entry-into-humans study in 70 healthy male subjects assessing tolerability, safety, pharmacokinetics and pharmacodynamics revealed that the doses tested (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 six days, showed similar results.
