Actelion and GlaxoSmithKline have discontinued development of their Phase III insomnia candidate, almorexant, following a review of clinical data. The drug, an orexin receptor antagonist, had been widely regarded by leading sleep disorder specialists as an innovative and promising insomnia treatment. Termination of the drug's development casts doubt over the future of the drug class.
The companies' decision to discontinue Phase III development of almorexant, a dual orexin receptor antagonist, follows a review of clinical studies which were conducted to further establish the clinical profile of the drug, including the tolerability profile. Speculation over almorexant's future initially arose in December 2009 when Actelion announced that although the drug had met its primary endpoint in a pivotal Phase III insomnia trial, "safety observations" were made that required further investigation.
Orexins (also known as hypocretins) are neuropeptides produced by the lateral hypothalamic neurons that were first described in the late 1990s. They have been shown to play a prominent role in both maintenance and wakefulness. With the prescription insomnia market currently dominated by non-benzodiazepines, particularly GABAa modulators, drugs belonging to the orexin receptor antagonist class represent the most novel candidates in development for the treatment of insomnia, a condition that is estimated to affect 33 million individuals across the seven major markets (the US, Japan, France, Germany, Italy, Spain, and the UK). Indeed, key opinion leaders interviewed by Datamonitor were unanimous in their view that orexin receptor antagonists are particularly promising potential treatments for insomnia.
Previously announced clinical trial data had indicated that almorexant had the potential to satisfy the unmet needs for a reduction in residual daytime sedation and lack of potential for tolerance and addiction. Had the "safety observations" of almorexant's Phase III trial been found to be non-serious in nature, Datamonitor estimates that the candidate had the potential to achieve revenues of $669m across the seven major markets excluding Japan by 2019. As such, the halting of almorexant's development has dashed Actelion's and GlaxoSmithKline's hopes of occupying a share of the $3.4bn insomnia market in the near to mid-term.
However, arguably the greater ramification of almorexant's termination is the doubt that it casts over the future of the orexin receptor antagonist drug class as a whole. The news will be of particular concern to Merck & Co., whose orexin receptor antagonist MK-4305 is presently undergoing Phase III clinical trials. Indeed, ascertaining the safety of MK-4305 should be a priority for Merck.
Following the discontinuation of three serotonin modulators in the insomnia pipeline over 2008-10, it remains to be seen whether the cessation of almorexant's development will signal the demise of the orexin receptor antagonists in this indication.