NEW YORK – A research team at Washington University School of Medicine is recruiting patients at risk for developing Alzheimer's disease in a Phase II clinical trial to study how a drug already approved for insomnia affects the development of the neurodegenerative disease.
Investigators aim to enroll about 200 patients in the study to test whether a dual orexin receptor antagonist (DORA), a class of drugs developed to treat insomnia, can decrease the rate of beta-amyloid accumulation in the brain — the surrogate endpoint based on which the US Food and Drug Administration granted therapies like Leqembi (lecanemab) and Aduhelm (aducanumab) accelerated approval.
DORAs block orexin, a chemical that promotes wakefulness. Past studies have suggested there may be a link between lack of sleep and dementia risk and that orexin may be involved in the development of Alzheimer's disease. Previous research has also suggested that DORAs can lower levels of amyloid-beta peptides, the main component of amyloid plaques that commonly accumulate in the brains of Alzheimer's patients. These deposits show up in patients' brains long before cognitive decline, though around 40 percent of patients with dementia don't have amyloid plaques, and some people who do have them have normal cognition.
In a proof-of-concept study led by Brendan Lucey, an associate professor of neurology at WashU who's also leading the Phase II trial, investigators enrolled 38 healthy volunteers between 45 and 65 years old and assigned them to receive two higher doses of a DORA called Belsomra (suvorexant), two lower doses of the drug, or a placebo. Investigators identified reductions in amyloid-beta in cerebrospinal fluid, as well as in phosphorylated tau, which is another biomarker protein linked with Alzheimer's.
"We don’t yet know whether long-term use [of suvorexant] is effective in staving off cognitive decline, and if it is, at what dose and for whom," Lucey said in a statement. "Still, these results are very encouraging. This drug is already available and proven safe, and now we have evidence that it affects the levels of proteins that are critical for driving Alzheimer’s disease."
In the new Phase II trial, investigators will randomize patients to either an experimental group that takes Belsomra daily for two years or a control group in which patients will take a placebo for that same period. Patients must have some level of amyloid-beta but no clinical signs of dementia to partake in the study. Investigators will use positron emission tomography (PET) scans to evaluate whether Belsomra-treated patients have lower levels of amyloid-beta in their brains over the study period than they did at baseline and compare these outcomes to patients in the placebo group.
Secondary outcomes include change in tau accumulation as measured by PET scans, change in amyloid-beta and tau as measured by blood and cerebrospinal fluid collection, and change in cognitive performance as measured by various cognitive tests.