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New medications offer hope in people with Narcolepsy and Idiopathic Hypersomnia

By Prof Ron Grunstein

Orexin is a brain chemical that promotes wakefulness and is absent low levels in classic narcolepsy (has cataplexy). Orexin levels are typically normal in Type 2 narcolepsy (no cataplexy) and idiopathic hypersomnia (IH) but some have argued that there is an orexin regulation problem, but data is lacking. However early trials by the Japanese pharmaceutical Takeda have shown benefits in narcolepsy 1 and 2 and IH with a drug that is an orexin agonist ie. a mimic of orexin. A very promising study of an orexin agonist, published in the New England Journal of Medicine, by Yves Dauvilliers and Emmanuel Mignot and colleagues was shown to markedly reduce sleepiness in Type 1 narcolepsy but unfortunately some patients developed abnormal liver function tests which led the drug to be withdrawn. Nat Marshall and I wrote an editorial in the Journal that highlighted the possibility that newer orexin-like drugs may be improvements without side effects. Recently, Takeda announced positive results from a randomized, double-blind, placebo-controlled trial TAK-861, a new orexin receptor 2 (OX2R) agonist, in patients with narcolepsy type 1 (NT1) and narcolepsy type 2 (NT2). In the narcolepsy type 1 trial TAK-861-2001 evaluated TAK-861 in 112 patients demonstrated a clinically meaningful improvement in objective and subjective measures of wakefulness and cataplexy compared to placebo after 8 weeks. The majority of patients who completed the trial entered a long-term extension study and larger longer-term studies are now being planned. TAK-861 was generally safe and well tolerated in both trials. No treatment-related serious adverse events were reported. In addition, no cases of abnormal liver function.

Unfortunately, Takeda does not plan to continue TAK-861 in NT2 presumably due to lack of positive results. However, Takeda and other companies have multiple other orexin agonists to trial in non-NT1 conditions and research is progressing including at our site*. Results from both trials will be presented at an upcoming scientific congress.

*The Woolcock institute has been running funded trials of orexin agonists. Learn more about the promising preliminary results here. Comment by Dr Nat Marshall re; the study published in the New England Journal by Yves Dauvilliers Emmanuel Mignot and colleagues. "The new class of drugs that have been developed based on the observation that Type 1 narcolepsy patients do not have any orexin are the Orexin Agonists. The trial in the NEJM reports on a formulation that has now been abandoned because of safety concerns but has a really quite amazing efficacy signal. Patients with narcolepsy who had objectively and subjectively very severe sleepiness had their ability to stay awake completely normalised in this trial. They also reported having a massive decrease in cataplectic attacks. The effect is massively superior to that seem in all other drugs for the condition. If it is possible to balance a formulation dose to make it safe but retain the efficacy signal it will be a game changer for the treatment of Narcolepsy.

As Ron Grunstein and I noted in the editorial we were lucky enough to be invited to write the preliminary evidence in other conditions of excessive daytime sleepiness (eg: idiopathic hypersomnia and Type 2 narcolepsy) indicates that you need a higher dose than you do in Narcolepsy to achieve the same results. Sadly that's probably going make it more difficult to get a safe and effective dose for other conditions such as sleep apnea, idiopathic hypersomnia, or Type 2 narcolepsy."


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