About Almorexant

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

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, 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.

Supporting Studies

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 again in a dose-dependent fashion to decrease latency to persistent sleep (LPS) and wake-after-sleep onset (WASO).

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. 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 healthy female and male volunteers receiving up to 1000mg for up to six days, showed similar results.

Milestones

• Project initiated in-house in 1998
• Entry-into-man study initiated 2005
• Phase III RESTORA study initiated 2007
• Patent protection will expire in 2025 at the earliest

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.