Recent Narcolepsy Breakthroughs

A recent study published in May 2023 by Ali Seifinejad et al. revealed new insights into the underlying causes of narcolepsy. The traditional theory of auto-immune destruction of hypocretin/orexin neurons has been challenged by the researchers’ discovery that a large number of these neurons are preserved in narcoleptic patients. However, the genes responsible for producing hypocretin/orexin were silenced and therefore not actively producing the neurotransmitter. Upon further investigation, they found that the protein-coding gene was in fact intact, but epigenetically silenced as represented by abnormal methylation patterns. These findings are extremely significant as it provides evidence opposing the traditional theory of auto-immune destruction of these neurons, suggesting that it is possible to reverse these changes in affected patients and open new avenues for narcolepsy treatments (Seifinejad, 2023). These findings were further supported by a publication from researchers in Tokyo in June, who found similar abnormal methylation in genes associated with Narcolepsy Type I (Yoshida-Tanaka, 2023).

Also announced in May 2023, Avadel Pharmaceuticals achieved FDA approval for their new medication Lumryz. This extended-release sodium-oxybate therapeutic is the first of its kind as it only requires a single dose to be taken at bedtime. Traditionally, sodium oxybate must be administered twice, with the first dose at bedtime and a repeat dose 2-4 hours later. This requires patients to rise in the middle of the night in order to experience the maximum therapeutic effects of a full dose. As explained by Dr. Michael J. Thorpy, M.D, Director at the Sleep-Wake Disorders Center at Montefiore Medical Center and Professor of Neurology at the Albert Einstein College of Medicine, “This long-awaited therapy for people living with narcolepsy fills a critical unmet need by avoiding the burden of a second middle-of-the-night dose that immediate-release oxybate products require. The once-at-bedtime dosing regimen of Lumryz may help restore a more natural sleep-wake cycle” (Avadel Pharmaceuticals, 2023).

Recent discoveries in narcolepsy research are challenging traditional approaches and paving the way for more targeted interventions. One area of promising research is the use of OX2R agonists, which have the potential to address the root causes of narcolepsy rather than just managing its symptoms. By targeting orexin receptors, these agonists offer a unique opportunity to restore disrupted neurochemical pathways, providing long-lasting relief. However, despite the impressive effectiveness of Takeda's OX2R agonist TAK-994 in treating key narcolepsy symptoms, concerns have been raised about its association with hepatotoxicity. The early termination of the Phase 2 and extension trials highlights the need for novel and well-tolerated OX2R agonists in the field of narcolepsy research (Takeda, 2023).

Researchers are working to uncover new biomarkers to differentiate narcolepsy due to the difficulty of diagnosing the disease. In a study published in Sleep in early 2023, researchers identified mean REM sleep duration as a particularly promising neurophysiological biomarker for identifying narcoleptic patients with hypocretin deficiencies. This groundbreaking finding challenges conventional diagnostic criteria and suggests that assessing REM sleep duration during the Multiple Sleep Latency Test (MSLT) could significantly enhance the accuracy of narcolepsy diagnosis. The study revealed that a mean REM sleep duration of ≥5.7 minutes in narcoleptic patients exhibited robust discriminatory power, with an AUC accuracy, sensitivity, and specificity values all nearing 0.80. Mean REM sleep duration has been identified as a promising biomarker of narcolepsy, and additional research is underway to explore other reliable markers that will accelerate diagnoses and reveal underlying components of this complex disorder (Lopez, 2023). In addition to sleep metrics, biomarkers of an electrophysiological nature are being discovered. In a recent study done in Italy, researchers explored the efficacy of muscle tone in determining narcolepsy. Measured by the atonia index during wakefulness (WAI), these researchers found significant changes in this metric between narcoleptic (both type I and type II) and control patients with other hypersomnias (Romigi, 2023). As researchers continue to unveil innovative biomarkers, the path toward more accurate and timely diagnosis of narcolepsy becomes increasingly illuminated, offering hope for enhanced patient care and a deeper understanding of this intricate disorder.

References

• Avadel Pharmaceuticals. (2023, May 1). Avadel Pharmaceuticals Announces Final FDA Approval of LUMRYZ™ (sodium oxybate) for Extended-Release Oral Suspension as the First and Only Once-at-Bedtime Oxybate for Cataplexy or Excessive Daytime Sleepiness in Adults with Narcolepsy [press release]. https://investors.avadel.com/news-releases/news-release-details/avadel-pharmaceuticals-announces-final-fda-approval-lumryztm

• Lopez, R., Barateau, L., Laura Rassu, A., Evangelista, E., Chenini, S., Scholz, S., Jaussent, I., & Dauvilliers, Y. (2023). Rapid eye movement sleep duration during the multiple sleep latency test to diagnose hypocretin-deficient narcolepsy. In Sleep (Vol. 46, Issue 1). Oxford University Press (OUP). https://doi.org/10.1093/sleep/zsac247

• Romigi A, Caccamo M, Testa F, et al. Muscle atonia index during multiple sleep latency test: a possible marker to differentiate narcolepsy from other hypersomnias. Clin Neurophysiol. 2023;149:25-31. doi:10.1016/j.clinph.2023.01.019

• Seifinejad, A., Ramosaj, M., Shan, L., Li, S., Possovre, M.-L., Pfister, C., Fronczek, R., Garrett-Sinha, L. A., Frieser, D., Honda, M., Arribat, Y., Grepper, D., Amati, F., Picot, M., Agnoletto, A., Iseli, C., Chartrel, N., Liblau, R., Lammers, G. J., … Tafti, M. (2023). Epigenetic silencing of selected hypothalamic neuropeptides in narcolepsy with cataplexy. In Proceedings of the National Academy of Sciences (Vol. 120, Issue 19). Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.2220911120

• Takeda Pharmaceutical Company. (2023, July 26). The New England Journal of Medicine Publishes Data from Phase 2 Study of First Oral Orexin Receptor 2 Agonist TAK-994 in Patients with Narcolepsy Type 1 [press release]. https://www.takeda.com/newsroom/newsreleases/2023/the-new-england-journal-of-medicine-publishes-data-from-phase-2-study-of-first-oral-orexin-receptor-2-agonist-TAK-994-in-patients-with-narcolepsy-type-1/

• Yoshida-Tanaka, K., Shimada, M., Honda, Y. et al. Narcolepsy type I-associated DNA methylation and gene expression changes in the human leukocyte antigen region. Sci Rep 13, 10464 (2023). https://doi.org/10.1038/s41598-023-37511-4