Novel Agent May Ease Circadian Rhythm Disorder in Alzheimer's

Megan Brooks

July 24, 2019

LOS ANGELES — An investigational agent may help regulate sleep in patients with Alzheimer's disease (AD) who have a disorder that disrupts sleep patterns, results of a small phase 2 study suggest.

Investigators found lemborexant (Eisai Inc), a dual orexin receptor antagonist, was beneficial in AD patients with irregular sleep-wake rhythm disorder (ISWRD), a common disorder in this patient population that has no effective treatment. 

"This pilot study provides preliminary evidence that lemborexant may help improve circadian rhythms to improve sleep patterns and may be a promising treatment for sleep problems in individuals with Alzheimer's disease," said lead investigator Margaret Moline, PhD, executive director of clinical development of Eisai's Neurological Business Group.

The findings were presented here at the Alzheimer's Association International Conference (AAIC).

Different From Insomnia

"ISWRD is a circadian rhythm sleep disorder that is different from insomnia," Moline told the briefing. ISWRD affects the entire 24-hour sleep-wake cycle. Individuals with the disorder tend to take numerous naps in a 24-hour period and are unable to sustain consolidated sleep at night. 

The disorder is common in patients with Alzheimer's disease dementia, "with no adequate pharmacological or non-pharmacological treatment," said Moline. However, recent evidence implicates orexin system dysfunction in ISWRD "and this is where lemborexant comes into play," she said.

The phase 2 study included 62 older adults meeting DSM-5 criteria for ISWRD and mild to moderate AD (Mini-Mental State Examination score 10-26). Participants were randomly assigned to receive various doses of lemborexant (2.5 mg, 5 mg, 10 mg, 15 mg) or placebo for 4 weeks. Participants wore an actigraph to track their sleep and awake times and these data were supplemented with a daily sleep diary completed by caregivers.

Compared with placebo, treatment with lemborexant 5-mg and 15-mg was associated with significantly lower nighttime activity levels and significantly higher relative amplitude, reflecting the strength of the circadian signal and differentiation between daytime and nighttime activity levels, Moline reported. "In patients with ISWRD, the amplitude is blunted," she noted.

There were also statistical trends toward less sleep fragmentation and higher total sleep time.

In addition, no serious adverse events were reported.

"We did not see any falls or confusion reported, and importantly there was no significant worsening of cognitive function," said Moline. Limitations of the study include the small sample size and short duration, she noted.

Promising Results

This was a "very detailed phase 2 [study] with some promising results," said briefing moderator David Knopman, MD, a clinical neurologist at the Mayo Clinic in Rochester, Minnesota, and member of the Alzheimer's Association Medical and Scientific Advisory Group.

The drug led to "positive alteration of the sleep-wake cycle and the results will inform a larger phase 3 study going forward that will be more definitive," said Knopman.

Lemborexant is currently under review with the US Food and Drug Administration (FDA) as a treatment for insomnia.

The study was supported by Eisai Inc and Purdue Pharma. Moline and five coauthors are employees of Eisai. Knopman has disclosed no relevant financial relationships.

Alzheimer's Association International Conference (AAIC) 2019: Abstract P2-617. Presented July 15, 2019.

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