Actelion's new dual orexin receptor antagonist (DORA), is orally active, effectively crosses the blood-brain barrier and is currently evaluated as a treatment for insomnia.

As part of its drug discovery efforts on G-Protein Coupled Receptors, Actelion has built a library of potent dual oral orexin receptor antagonists. These compounds are active on both OX1 and OX2, the receptors which mediate the actions of orexins. Actelion’s work with dual orexin receptor antagonism has demonstrated that blocking the activity of the orexin receptors offers the potential to restore normal physiological sleep.

CURRENT STATUS

In July 2016, Actelion announced that the company is initiating a Phase II program with its new dual orexin receptor antagonist in patients with insomnia.

The Phase II program consists of two studies, one in adult and one in elderly patients. It is designed to evaluate the effect of Actelion’s DORA versus placebo on sleep maintenance and sleep initiation, as well as next-day residual effect and next-day performance. The adult study will also include an active reference arm with zolpidem, as the most widely used insomnia treatment targeting GABA-A receptors. Both studies will also generate information on sleep architecture and sleep quality. 

The first study is a multi-center, double-blind, randomized, placebo-controlled, active reference, parallel-group, dose-response study to evaluate the efficacy and safety of Actelion’s DORA. The study is expected to commence enrollment in Q4 2016 and will recruit approximately 300 adult patients diagnosed with insomnia. The study will comprise 6 treatment arms: placebo; zolpidem; 5, 10, 25, and 50 mg of Actelion’s DORA. Treatment duration is 4 weeks. The primary endpoint is wake-time after sleep onset (WASO) at day 1 & 2. 

The second study is a multi-center, double-blind, randomized, placebo-controlled, crossover, dose-response study to evaluate the efficacy and safety of Actelion’s DORA. The study is also expected to commence enrollment in Q4 2016 and will recruit approximately 50 elderly patients diagnosed with insomnia. The study has a 5-period crossover design with 5 treatment arms: placebo; 5, 10, 25 and 50 mg of Actelion’s DORA. Treatment duration in each period is 2 days. The primary endpoint is WASO at day 1 & 2. 

Secondary objectives of both studies include evaluation of Actelion’s DORA versus placebo on latency to persistent sleep (LPS) as well as subjective latency to sleep onset (sLSO) and subjective WASO (sWASO). Safety and tolerability will also be evaluated.

 

AVAILABLE CLINICAL DATA

Data from an extensive Phase I program have confirmed the optimal pharmacokinetic and pharmacodynamic profile for a sleep medication, together with excellent safety and tolerability.

Milestones

2014 > Initiation of Phase I clinical program

KEY SCIENTIFIC LITERATURE

Brisbare-Roch C. et al. Nat Med. 13(2):150-5; 2007.

Hoever P et al. Clin Pharmacol Ther Clin Pharmacol Ther. 2012; 91(6); 975-985.

Roth T. 2007;3 Suppl 5:S7-10.