Enrollment Begins for Phase 1 Study of Eisai’s Orexin-2 Receptor Agonist E2086 in Narcolepsy

Lynn Kramer, MD

Eisai recently announced open enrollment for its phase 1 study, study 101 (NCT06462404), which will investigate the efficacy and safety of E2086, an investigational selective orexin-2 receptor, as a potential treatment in patients with narcolepsy.¹

According to the company, preclinical studies have shown statistically significant increases in time spent awake and significant reductions in rates of cataplexy with E2086. In narcolepsy, excessive daytime sleepiness and cataplexy are reported in associated with low levels of the neurotransmitter orexin. Based on E2086’s mechanism of action, the hypothesis is that this agent will compensate for the loss of orexin in patients living with the condition.

The primary purpose of the newly launched phase 1 study is to evaluate the efficacy of single oral doses of E2086 compared with placebo in the treatment of excessive daytime sleepiness as assessed by the Maintenance of Wakefulness Test in adults with narcolepsy type 1. This randomized, double-blind, single-dose trial is anticipated to enroll 40 individuals with the disorder to test the effects of 3 different dose strengths of E2086 against placebo.

"The availability of drugs like E2086 will open a new era in the treatment of narcolepsy and potentially other disorders of hypersomnolence," Lynn Kramer, MD, FAAN, chief clinical officer at Eisai, said in a statement.¹ "By addressing the deficiency of orexin with what is in essence a replacement therapy, E2086 will hopefully provide a meaningful impact on the symptoms and the consequences associated with narcolepsy to improve the quality of lives of these patients."

READ MORE: FDA Approves Pitolisant for Excessive Daytime Sleepiness in Pediatric Narcolepsy

The study will enroll those with a diagnosis of narcolepsy type 1 defined by a history of daily periods of irrepressible need to sleep, or daytime lapses into sleep, occurring for at least 3 months, as well as a history of cataplexy. These patients will need at least 1 of the following: a multiple sleep latency test of less than or equal to 8 minutes and 2 or more sleep onset REM periods (SOREMPS) on MSLT performed according to standard techniques, or one or SOREMPs within 15 minutes of sleep onset on screening nocturnal polysomnography.²

There are a number of exclusion criterias for the study, including females who are breastfeeding or pregnant at screening, those with a history of myocardial infarction, ischemic heart disease, or cardiac failure. In addition, the study excludes those with a history of clinically significant arrhythmia or uncontrolled arrhythmia, patients with any history of psychiatric disease or any current psychiatric symptoms as indicated by a standard screening tool. Furthermore, the study precludes those with a history of formally diagnosed moderate to severe obstructive sleep apnea, current use of continuous positive airway pressure, or symptomatic restless legs syndrome.

Narcolepsy is a rare, chronic, central nervous system disorder of hypersomnolence characterized by excessive daytime sleepiness, which can be associated with cataplexy, hypnagogic or hypnopompic hallucinations, sleep paralysis, and disrupted night-time sleep. There are 2 major types of narcolepsy: narcolepsy type 1 and narcolepsy type 2, the former distinguished by symptoms of cataplexy and the loss of orexin-producing neurons in the lateral hypothalamus. Low to absent orexin levels in the cerebrospinal fluid support a diagnosis of narcolepsy type 1.

REFERENCES
1. Eisai to begin enrolling study in patients with narcolepsy. News release. Eisai. July 8, 2024. Accessed August 15, 2024. https://www.prnewswire.com/news-releases/eisai-to-begin-enrolling-study-in-patients-with-narcolepsy-302190859.html
2. A Study to Evaluate the Efficacy, Safety, and Tolerability of E2086 Compared to Placebo and Active Comparator in Adult Participants With Narcolepsy Type 1. Clinicaltrials.gov. Updated June 17, 2024. Accessed August 15, 2024. https://clinicaltrials.gov/study/NCT06462404?term=NCT06462404&rank=1