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World-first research program into drugs that could help people suffering from narcolepsy

Monday, September 11, 2023

Trials of a drug that can mimic the missing neurotransmitter responsible for the debilitating sleep condition narcolepsy are underway in Sydney, opening the gate for an effective treatment.  

The Woolcock Institute of Medical Research’s Professor Ron Grunstein, a sleep expert of more than 30 years, says the Woolcock has commenced a world-first program of research into orexin agonists, – a class of drugs that stimulate receptors for the neurotransmitter orexin – that is absent or lacking in patients with narcolepsy.  

Narcolepsy (Type 1 and Type 2) – a chronic condition that affects up to 6,000 Australians – is characterised by excessive daytime sleepiness, sleep paralysis, dream-like hallucinations, automatic behaviour, and, in the case of about 60 to 70 per cent of patients, cataplexy – the partial or total loss of muscle control in response to emotion such as laughter.  

Cataplexy, hallucinations and sleep paralysis are all manifestations of rapid eye movement sleep intruding into wakefulness. 

Little is known about the mechanisms that underpin this disorder, but patients with narcolepsy and cataplexy have low or undetectable levels of orexin in the fluid surrounding the brain. 

Only a small group of neurons in the lateral hypothalamus (a part of your brain that controls behaviours like sleep, hunger, body temperature and arousal) make orexins. In turn, these neurons project widely to brain centres that promote alertness. The orexin signalling to other parts of the brain prevent cataplexy, hallucinations and sleep paralysis.  

In classic narcolepsy, there’s a degeneration or complete loss of orexin neurons, meaning that people with narcolepsy don’t make much or any orexin. In some other forms of severe sleepiness, there is a problem with orexin neuron signalling. 

“There are a few companies developing different orexin-like drugs, and preliminary studies show that these drugs have a remarkable ability to keep people with narcolepsy awake and productive,” Professor Grunstein says.

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“We are excited about the possibility of an affordable and effective treatment for a condition that is dangerous and devastating. Narcolepsy causes people to fall asleep without realising and can result in people losing all muscle tone after experiencing strong emotions like laughing, anger and so on. As well, there are many more people with other sleepiness disorders related to problems with orexin transmission in their brains.”  

A recent Phase 2 clinical trial of an oral orexin agonist (TAK-994) for the treatment of narcolepsy, randomly assigned 73 patients to different drug doses or matching placebo, for eight weeks. Writing about the trial in a recent editorial for The New England Journal of Medicine (NEJM), the Woolcock’s Professors Grunstein and Nathaniel Marshall argue that despite the trial being halted in October 2021 after a rise in liver enzymes, “the efficacy signal of reducing most aspects of narcolepsy in the trial was particularly strong.”

They concluded that “despite the halt in the development of TAK-994, there is a strong rationale to pursue the use of orexin agonists for the treatment of narcolepsy type 1, and perhaps other disorders, such as shift-work sleep disorder or jet lag, for which trials are being undertaken”. 

The Woolcock was recently involved in a global trial of the long-acting form of the drug sodium oxybate, currently being introduced as a first-line medication for narcolepsy in countries overseas which can improve sudden loss of muscle control (cataplexy) and help patients sleep at night. 

Short-acting sodium oxybate, classed as a controlled substance in Australia (Schedule 8) is only approved for use under special circumstances. It is also not included on the Pharmaceutical Benefits Scheme, so can cost a patient $15,000 to $22,000 per year, putting it out of reach for many people. 

"The most pressing need is for people with narcolepsy to be able to access the best current medications for them,” Professor Grunstein says.  

Professor Grunstein says that although Australia boasts a first-class healthcare system, our approach to narcolepsy management is manifestly inadequate, leaving a group of people who are, in many cases, unable to work and limited in how they can live their lives.’  

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