Almorexant

Almorexant is a first-in-class, dual 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. 

Almorexant in development for insomnia

Current status
Almorexant statusAlmorexant 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 met its primary endpoint, superiority of the dual orexin receptor antagonist almorexant compared to placebo on objective and subjective wake after sleep onset (WASO). The finding was highly significant (p<0.001). In addition, several secondary endpoints of the study were met with statistical significance.

In RESTORA 1, the use of almorexant was well-tolerated. However, certain safety observations were made. As a result the non-pivotal part of the clinical program was expanded during the first half of 2010 to better understand the safety and tolerability profile of this innovative compound. In Q1 2011, data from this non-pivotal program should allow Actelion and its collaboration partner GSK to decide on the initiation of the remaining Phase III studies. The almorexant development program was recently discussed at a meeting with the US Food and Drug Administration.

Available clinical data
RESTORA 1 was a multi-center, double-blind, randomized, placebo-controlled, active reference (zolpidem), parallel-group polysomnography study to evaluate efficacy and safety of 16-day oral administration of almorexant 200mg and 100mg in adult 709 patients with chronic primary insomnia. Enrolment took place in 90 clinical study centers in Australia, Europe and Israel.

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.

Milestones
2009 – RESTORA 1 meets primary end-point in two week Phase III study 
2008 – Exclusive world-wide (excluding Japan) collaboration with GlaxoSmithKline initiated
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.