A major step forward in the treatment of narcolepsy

Difficulty staying awake may seem trivial, but it's the main symptom of one of the most severe sleep disorders: narcolepsy. In Montpellier, the Centre de référence des narcolepsies et hypersomnies rares (Inserm/University/CHU de Montpellier) headed by Yves Dauvilliers is conducting cutting-edge research into this disease. The neurologist and his collaborators, in partnership neurologist and his colleagues, in partnership with the Takeda laboratory, have just carried out a groundbreaking study into a promising treatment. The study was published in the New England Journal of Medicine on July 27, 2023.

Nearly 20,000 people in France suffer from narcolepsy, a condition that generally manifests itself between the ages of 15 and 20. While difficulty staying awake is the main symptom of this neurological condition, it is not the only one. Sleepiness can sometimes be accompanied by weight gain, hallucinations, sleep paralysis and frequently cataplexy, in other words, " loss of muscle strength linked to favorable emotions such as laughter ", explains Yves Dauvilliers of Montpellier University Hospital, and team leader of the Institut des Neurosciences de Montpellier, Inserm, University of Montpellier.

Narcolepsy is an autoimmune disease of genetic and environmental origin, whose symptoms are caused by the destruction of a particular category of neurons: those which synthesize orexin, otherwise known as hypocretin, a neurotransmitter whose main role is to stimulate wakefulness. 80,000 neurons are destroyed in narcolepsy patients, who therefore lack orexin. As a result, it is impossible for them to maintain this waking state for long.

Patients declare themselves cured

Yves Dauvilliers and his colleagues tested a new treatment developed by the Takeda laboratory, an agonist of orexin 2 receptors, " a molecule which acts like a key similar to orexin and therefore has the same effects on the body ". While an equivalent treatment had already been tested by intravenous injection, for the first time it was given to patients in oral form. " They were divided into three groups, receiving doses of 30 mg, 90 mg or 120 mg of this molecule called TAK-994, and one group with a placebo ", explains Yves Dauvilliers. And in terms of improvement, the results were spectacular: "we didn 't just see a simple improvement in symptoms, for the first time, patients simply felt cured ".

Although the clinical trial had to be stopped prematurely due to hepatic side-effects in some patients, it nevertheless opens the door to real hope of a cure for all narcoleptics who struggle to stay awake. " We are already working on a new agonist with greater affinity for the orexin 2 receptor, and which would therefore have fewer side effects," explains Yves Dauvilliers.

Pending the arrival of this future treatment, the neurologist stresses the importance of early diagnosis of the disease. It's important to understand that sleeping in class when you're young can reveal an underlying illness," insists Yves Dauvilliers. Today, on average, it takes 8 years to diagnose narcolepsy, and only 1/3 of patients are diagnosed, which is far too few.

Oral Orexin Receptor 2 Agonist in Narcolepsy Type 1, Y. Dauvilliers, E. Mignot, R. del Río Villegas, Y. Du, E. Hanson, Y. Inoue, H. Kadali, E. Koundourakis, S. Meyer, R. Rogers, T.E. Scammell, S.I. Sheikh, T. Swick, Z. Szakács, P. von Rosenstiel, J. Wu, H. Zeitz, N.V. Murthy, G. Plazzi, and C. von Hehn. July 27, 2023, N Engl J Med 2023; 389:309-321 DOI: 10.1056/NEJMoa2301940