LAS VEGAS – With the exception of memantine, about 30 clinical trials of agents intended to halt the progression of Alzheimer’s disease have failed in the past decade.
"We’ve attacked every process you can think of in the amyloid cascade, but it’s possible that maybe these were just the wrong medications," Dr. Dylan P. Wint said at the annual psychopharmacology update held by the Nevada Psychiatric Association.
Dr. Dylan Wint
According to retrospective analyses, 20-30% of people diagnosed with Alzheimer’s disease (AD) turned out to not have the condition, said Dr. Wint, director of the fellowship in behavioral neurology and neuropsychiatry at the Las Vegas–based Cleveland Clinic’s Lou Ruvo Center for Brain Health. This suggests that "we may be doing trials on the wrong patients because of inadequate identification of the underlying pathology," he said. The focus on beta-amyloid also could be misguided, he suggested. "There is a strong possibility that we have the wrong hypothesis. Maybe attacking the amyloid is not going to make a dent in what happens with the disease overall. It turns out that amyloid pathology doesn’t correlate very well with symptoms of AD. Tau is much more associated with AD symptoms in terms of its distribution, compared with amyloid."
On the other hand, Dr. Wint pointed out that genetic mutations that cause Alzheimer’s disease are related to amyloid processing. Other processes that could have an impact on AD and warrant investigation include quality of cerebral cells, viability of neurons, and outgrowth of neurites, he added.
Promising AD biomarkers being studied in clinical trials such as brain imaging techniques, blood tests, and genetic-risk profiling might help clinicians identify the disease before symptoms start. "Biomarkers can help us to [recruit] patients who are more suited for clinical trials," added Dr. Wint, who is also director of education in neurodegeneration at the center. "They can help us verify the disease process and measure the severity of the disease – not just symptoms – and we can classify patients by the biomarker."
Emerging AD therapies in the pipeline can be classified as symptomatic (targeting cognition and behavior), disease-modifying (anti–beta-amyloid, anti-tau, and promoting neuroprotection), and regenerative (reversing the disease with stem cells and growth factors). According to Dr. Wint, disease-modifying treatments currently or recently in phase III trials include solanezumab, gantenerumab, albumin plus immunoglobulin, thalidomide, TRx0237, masitinib, and epigallocatechin gallate. Behavioral management agents in phase III trials include bupropion (targeting apathy), mirtazapine (insomnia), citalopram (agitation), and brexpiprazole (agitation). Meanwhile, cognitive enhancement agents being studied in phase III trials include nasal insulin, caprylic triglyceride, and coconut oil.
Dr. Wint said he and other researchers currently take "a multiple shots on goal approach" to advancing the understanding of AD. "That means trying things from all of these categories," he said. "At the Lou Ruvo Center, we’re looking at diagnosis through blood testing, studying the impact of the oral cancer drug bexarotene on amyloid, medical foods, IV [intravenous] medications, the impact of a magnetic stimulation device on information processing, and brain imaging as a way to diagnose candidates for clinical trials."
Dr. Wint disclosed that he has received speakers fees from Accera and has consulted for Teva Pharmaceutical Industries.