Stanford researcher shows once-nightly narcolepsy drug is safe, effective

A new version of a narcolepsy drug that patients take once at bedtime — rather than at bedtime and again in the middle of the night — safely and effectively improved symptoms in a trial led by a researcher at Stanford Medicine.

The drug the researchers were investigating, ON-SXB, is an extended-release version of sodium oxybate, which requires twice-nightly dosing. Sodium oxybate is approved by the Food and Drug Administration for the treatment of multiple narcolepsy symptoms, including excessive daytime sleepiness and cataplexy — sudden muscle weakness while awake.

In the trial, ON-SXB decreased cataplexy attacks and daytime sleepiness more effectively than a placebo, while increasing clinicians’ ratings of the overall condition of study participants. Its safety profile was favorable, with side effects that were similar to those caused by the twice-nightly version of sodium oxybate. Eliminating the need for a second dose at night, ON-SXB could help patients adhere to the medication regimen, reduce the risk of falls leading to injury, and improve nocturnal sleep and overall quality of life.

“Sodium oxybate has largely become a first-line treatment for patients with narcolepsy,” said Clete Kushida, MD, PhD, a professor of psychiatry and behavioral sciences. “Clinicians can be confident that a single bedtime dose of sodium oxybate has demonstrated efficacy for both objective and subjective symptoms of narcolepsy.”

The study was published Aug. 6 in Sleep. Kushida is the lead author.

Seeking sound sleep

Narcolepsy is a chronic neurological disorder that affects between 135,000 and 200,000 people in the U.S. In addition to excessive daytime sleepiness and cataplexy, symptoms include disrupted nighttime sleep, sleep paralysis, and hallucinations when falling asleep or waking up. All patients experience excessive daytime sleepiness, which can manifest as sleep attacks that last several seconds or minutes and can occur while talking, eating or driving.

Cataplexy, which is another common symptom, is often triggered by strong emotions and sometimes causes falls. This collection of features can interfere with psychological and cognitive function and development; it can also severely impede daily life, including school attendance, employment and social activities.   

Sodium oxybate is effective at treating multiple narcolepsy symptoms, including disrupted nighttime sleep. But because its half-life is approximately 30 minutes to 1 hour, a second dose is required 2 ½  to 4 hours after the first dose. Waking in the middle of the night to take the medication can be highly disruptive, especially considering that patients typically already experience fragmented sleep and poor sleep quality.

A study in Europe showed that 27% of patients with narcolepsy did not take sodium oxybate on the recommended time schedule. When patients need to take medications more than once daily, they tend to miss doses: This problem has been seen with other conditions, including depression, schizophrenia, epilepsy, Type 2 diabetes, cardiovascular disease, chronic obstructive pulmonary disease and HIV.

“A medication that is taken twice daily — in the morning and evening — is more challenging than a once-daily medication, but it’s even more problematic for a chronic medication requiring middle-of-the-night awakening,” Kushida said. “Although the labeling advises patients to remain in bed to take the second dose, falls leading to injury and, in some cases, hospitalization have been reported when patients rise from bed.”

No-awakening alternative

The trial was conducted from November 2016 to March 2020 at 71 centers in the United States, Australia, Canada and Europe. In total, 222 narcolepsy patients, ages 16 or older, were randomly assigned to take ON-SXB, in varying amounts, or a placebo.

Compared with placebo, participants on the three highest doses of ON-SXB had significantly less daytime sleepiness, a decrease in weekly cataplexy attacks, lower self-rated sleepiness in everyday situations, and higher overall condition scores from their clinicians. For example, 72% of participants taking the highest dose of ON-SXB were considered much or very much improved, compared with 31.6% in the placebo group.

The side effects of ON-SXB are similar to those of the twice-nightly version of sodium oxybate and include nausea, headache, vomiting, dizziness, involuntary urination and decreased appetite. But with ON-SXB, rates of headaches, nausea and dizziness were lower.

ON-SXB is under review at the FDA for the treatment of excessive daytime sleepiness and cataplexy in adults with narcolepsy. It has received orphan drug designation from the FDA because it may be clinically superior to the twice-nightly formulation of sodium oxybate already approved for the same condition. Orphan status is provided to drugs for the treatment, diagnosis or prevention of rare diseases that either affect fewer than 200,000 people in the United States, or are otherwise not expected to recover the development and marketing costs. Drug companies receive financial benefits for developing orphan drugs.

 “If approved, ON-SXB may be a major advance for patients experiencing the burdensome symptoms of narcolepsy and for physicians who manage their patients with this chronic, incapacitating sleep disorder,” Kushida said.

Researchers from the University of Toronto; Henry Ford Health System; Montefiore Medical Center; Sleep Management Institute; Florida Pediatric Research Institute; Neurotrials Research Inc.; Ohio Sleep Medicine and Neuroscience Institute; Avadel Pharmaceuticals; and Gui-de-Chauliac Hospital also contributed to the study.

The work was supported by Avadel Ireland.