Narcolepsy: Exploring Current Research and Innovation

Narcolepsy is a chronic neurological disorder characterized by the brain’s impaired ability to regulate a normal sleep-wake cycle. Narcolepsy is characterized by excessive daytime sleepiness (EDS), as well as sudden loss of muscle tone and cataplexy (weakness), sleep paralysis, hallucinations, fragmented sleep, and insomnia. Narcolepsy is characterized into two types- Type 1 with cataplexy and Type 2.

It has been noted that nearly all patients with Type 1 narcolepsy (with cataplexy) display abnormally low levels of hypocretin or orexin, which are neuropeptide hormones produced in the hypothalamus that promote wakefulness and regulate the sleep cycle. Understanding this mechanism has opened new avenues for targeted therapies aimed at compensating for this deficiency and improving symptoms associated with narcolepsy. 

Current treatments often use stimulants as the first line of treatments, as they help to manage excessive daytime sleepiness. These treatments include medications such as Modafinil (Provigil), Armodafinil (Nuvigil), and Solriamfetol (Sunosi). Additionally, there are also stronger stimulants for patients where this is not as effective, however these have negative side effects. Antidepressants are also prescribed for the associated symptoms of cataplexy and muscle weakness, common in Type 1 Narcolepsy, these are either tricyclics or selective serotonin reuptake inhibitors. The mechanisms for these help patients modulate their moods and reduce cataplexy triggers. For more information about the current treatment options and its limitations, visit our article. 

Recent advancements in pharmacology and treatment for narcolepsy focus on novel mechanisms of action that target Orexin receptors. Orexin receptor agonists, such as the investigational drug TAK-925, aim to directly address the hypocretin deficiency by stimulating orexin receptors (Takeda,2024). H3 receptor antagonists, like pitolisant (WAKIX®), work by enhancing histamine release, thereby promoting wakefulness (Harmony Biosciences,2021). Gene replacement therapies are also being explored, with the goal of restoring hypocretin production by introducing functional genes into the patient's neurons.

Key Events:

• Alkermes: On April 24, Alkermes announced the initiation of the Vibrance-1 Phase 2 study evaluating ALKS 2680, an oral orexin 2 receptor (OX2R) agonist, for the treatment of narcolepsy type 1 (NT1). This study will compare the safety and efficacy of ALKS 2680 to a placebo in NT1 patients . Previously, on April 10, Alkermes reported positive topline results from a Phase 1b study of ALKS 2680, demonstrating improved wakefulness in patients with narcolepsy type 2 and idiopathic hypersomnia.

• Harmony Bioscience: On April 11, Harmony Biosciences announced an exclusive agreement to develop and commercialize TPM-1116, a highly potent and selective oral orexin-2 receptor agonist . Harmony’s existing medication, WAKIX® (pitolisant), is already approved by the U.S. Food and Drug Administration for the treatment of excessive daytime sleepiness or cataplexy.

• Zevra Therapeutics: On March 26, Zevra Therapeutics announced data from the Phase 2 clinical trial of KP1077 for idiopathic hypersomnia.

• Axsome Therapeutics: On March 25, Axsome announced that AXS-12 achieved the primary endpoint in the Symphony Phase 3 trial in narcolepsy type 1 . Additionally, Axsome reported results from the CRESCENDO narcolepsy patient survey, highlighting unmet needs in treated narcolepsy type 1 patients.

Innovations in wearable technology have significantly enhanced the ability to monitor and measure sleep patterns in individuals with narcolepsy. Devices capable of conducting polysomnography outside the clinical setting and Multiple Sleep Latency Tests (MSLT) have become more accessible. These technologies provide detailed insights into sleep patterns and help tailor treatments more effectively.

Neurobit’s work includes developing advanced algorithms for sleep data analysis and identification of sleep biomarkers to improve both diagnosis and ongoing management of narcolepsy. 

Emerging research is exploring the relationship between narcolepsy and cardiovascular health, suggesting that individuals with narcolepsy may have an increased risk of cardiovascular disease. In particular, Dr. Christopher Kaufmann presented groundbreaking research during SLEEP2024 conference, which showcased the association between narcolepsy and cardiovascular disease, highlighting narcolepsy as an independent risk factor for cardiovascular disease(Kaufmann,2024).Understanding this link could lead to comprehensive treatment plans that address both sleep and cardiovascular health. Additionally, there is growing interest in pediatric narcolepsy, aiming to improve early diagnosis and strategies for children affected by the disorder.

The future of narcolepsy treatment looks promising, with ongoing research and innovative approaches paving the way for better management and therapies. Continued support for research and development will ensure that individuals with narcolepsy can look forward to improved outcomes and a higher quality of life.

References:

“Alkermes Announces Initiation of Vibrance-1 Phase 2 Study Evaluating Alks 2680 for the Treatment of Narcolepsy Type 1.” Alkermes plc. Accessed June 13, 2024. https://investor.alkermes.com/news-releases/news-release-details/alkermes-announces-initiation-vibrance-1-phase-2-study.

Derman, Chelsie. “AXSOME Therapeutics Announces New Symphony, Crescendo Data in Narcolepsy.” HCP Live, March 25, 2024. https://www.hcplive.com/view/axsome-therapeutics-announces-new-symphony-crescendo-data-narcolepsy.

Harmony Biosciences. “Harmony Biosciences to Present WAKIX® (PITOLISANT) Efficacy and Safety Data at Upcoming 2021 American Psychiatric Association Annual Meeting.” Harmony Biosciences, 2021. https://www.harmonybiosciences.com/newsroom/harmony-biosciences-to-present-wakix-r-pitolisant-efficacy-and-safety-data/.

“News Releases.” Harmony Biosciences, June 5, 2024. https://ir.harmonybiosciences.com/news-events/news-releases.

Takeda . “Takeda’s TAK-861 Phase 2b Late-Breaking Data Presentations at Sleep 2024 Demonstrate Clinically Meaningful Impact of Oral Orexin Agonist in Narcolepsy Type 1 Compared to Placebo.” Takeda Pharmaceuticals: Global Homepage, 2024. https://www.takeda.com/newsroom/newsreleases/2024/tak-861-data-at-sleep-2024-on-narcolepsy-type-1/.

Zevra Therapeutics. “Zevra Therapeutics Announces Top-Line Data from the Phase 2 Clinical Trial of KP1077 for Idiopathic Hypersomnia.” GlobeNewswire News Room, March 26, 2024. https://www.globenewswire.com/news-release/2024/03/26/2852762/0/en/Zevra-Therapeutics-Announces-Top-Line-Data-from-the-Phase-2-Clinical-Trial-of-KP1077-for-Idiopathic-Hypersomnia.html.