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Research Update: Orexin agonists for Narcolepsy and Idiopathic Hypersomnia

From Dr Julia Chapman PhD, Post-doctoral Research Fellow, Woolcock Institute of Medical Research


Orexin is a tiny molecule close to the heart of anyone who lives with narcolepsy. It was discovered simultaneously by 2 research groups in 1998, and hence given 2 names; orexin and hypocretin. It is known that there are two subtypes of orexin – Orexin A and Orexin B. There are also two subtypes of orexin receptors – OX1 and OX2. These receptors have some common and some different effects including wakefulness, arousal and appetite and are located in different areas of the body and brain. OX2 receptors play the major role in the maintenance of wakefulness.


Drug developers have long attempted to create a molecule that is stable enough to be taken by mouth, is specific enough to activate only those receptors that effect the cataplexy and daytime sleepiness symptoms of narcolepsy, without adversely affecting other body systems. We are now at the precipice of drug discovery, with several pharmaceutical companies competing to be the first to market with a novel, selective OX2 receptor agonist, which could revolutionise the treatment of narcolepsy, idiopathic hypersomnia, and potentially other disorders of daytime sleepiness.


As this new class of drug will specifically target OX2 receptors, it seems these new medications will have limited impact on eating behaviours or other body systems regulated by the OX1 receptor. In fact, early animal studies of this class of drug have been very promising in showing that they reduce cataplexy, reduce daytime sleepiness and do not induce any reward-seeking behaviour (i.e. not likely to cause drug dependence). Additionally, early clinical trials of a drug in this class (danavorexton- intravenously injected drug, not progressing to market) reduced daytime sleepiness to nil on the maintenance of wakefulness test in some patients.


What is also promising for people who live with narcolepsy without cataplexy or idiopathic hypersomnia is that in early animal studies where they trialled these drugs in animals without orexin deficiency, there is still a wakefulness-promoting effect, albeit at higher doses than required in narcolepsy type 1.


The Woolcock Institute of Medical Research is involved in the investigation of 2 new orexin agonists, with two clinical trials currently underway. Anyone with Narcolepsy Type 1, Narcolepsy Type 2 or Idiopathic Hypersomnia who is potentially interested in participating can email woolcock.narcolepsy@woolcock.org.au to find out more information.  Potential participants from outside Sydney who are willing to travel to Glebe for study visits may be considered (approval process required).


It is still early days with the ongoing research, but Australian researchers and physicians are enthusiastic about the emerging research in this area and are excited by the opportunity to participate in this global research. In addition, through undertaking these trials in Australia, researchers and physicians expect that it will make for a smoother drug registration process in the years to come.  We all hope that these drugs may eventually change the lives of people living with narcolepsy and IH.

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