Seizure drug shows promise in those without genetic risk

• For many people, mild cognitive impairment can be the first sign of Alzheimer’s disease.
• Researchers from AgeneBio and Johns Hopkins University are examining the use of a once-a-day investigational medication to treat amnestic mild cognitive impairment due to Alzheimer’s disease.
• Scientists found the drug helped slow brain atrophy progression in people with mild cognitive impairment due to Alzheimer’s disease who are not carriers of the APoE-4 genetic variant.

“Our studies have shown that patients with mild cognitive impairment, in addition to having amyloid and tau pathology, also show hyperactivity in an area of the brain called the hippocampus which is a structure critical for creating and retrieving memories,” Michela Gallagher, PhD, CEO and founder of AgeneBio, and Krieger Eisenhower Professor of Psychological and Brain Sciences at Johns Hopkins University explained to Medical News Today.

“The hyperactivity in this brain region contributes to the memory impairment these patients are experiencing and likely contributes to the disease progressing,” she explained.

Researchers found this new drug — which is an extended release form of the epilepsy medication levetiracetam — helped slow brain atrophy progression in people with mild cognitive impairment due to Alzheimer’s disease who are not carriers of the APoE-4 allele, a genetic variant that linked to increased Alzheimer’s disease risk.

This study is the phase 2b part of the HOPE4MCI clinical trial that evaluated the use of the investigational drug known as AGB101 to treat mild cognitive impairment in 164 people with Alzheimer’s disease.

“AGB101 is a once-a-day tablet formulation of an anti-seizure medication that quiets this hyperactivity in the brain and brings it down to levels we see in cognitively normal older adults,” Gallagher said.

“AGB101 was developed to treat hippocampal hyperactivity in adults and this clinical trial was focused on testing its efficacy in patients with mild cognitive impairment including both carriers and non-carriers of the ApoE-4 allele,” Arnold Bakker, PhD, associate professor of psychiatry and behavioral sciences, Biomarker Core Leader of the Johns Hopkins Alzheimer’s Disease Research Center at Johns Hopkins University, and lead author of this study explained to MNT.

During this study, Bakker said they found that study participants with mild cognitive impairment who were non-carriers of ApoE-4 treated with AGB101 showed a 40% reduction in progression on the Clinical Dementia Rating scale over 18 months compared to participants who were treated with placebo.

“This represents a meaningful retention of cognitive and daily functioning for patients over this period,” he added.

“Slowing progression in the relatively early mild cognitive impairment phase of disease will allow individuals to sustain independent living and delay the onset of dementia, reducing the number of individuals requiring nursing home care,” Gallagher also noted.

Additionally, scientists discovered that in people not carrying the ApoE-4 allele, AGB101 significantly reduced atrophy of the entorhinal cortex of the brain, which is the main connection to the hippocampus and plays an important role in memory and time perception.

“The entorhinal cortex is a brain area immediately adjacent to the hippocampus and has been recognized for decades as the area where Alzheimer’s disease pathology accumulates very early in the disease and the brain region that shows consistent and significant atrophy as the disease progresses. Slowing atrophy in this region is generally considered evidence of slowing disease progression.”

“Our findings showed that AGB101 treatment, in addition to having a clinical-cognitive benefit, also slowed tissue loss in this brain region, providing evidence of slowing disease progression,” he added.

“This study showed that in patients with mild cognitive impairment who are non-carriers of ApoE4, AGB101 not only matched the efficacy of FDA [Food and Drug Administration]-approved biologics in clinical-cognitive progression in prodromal Alzheimer’s disease, but surpassed any currently published data for Alzheimer’s disease therapeutics by significantly reducing atrophy of the entorhinal cortex, a key marker of disease progression in mild cognitive impairment due to Alzheimer’s disease, suggesting the treatment slows neurodegeneration,” Gallagher said.

“Although additional studies are needed, its potentially substantial effect in ApoE-4 non-carriers together with the limited side effects in this population, holds significant promise for this approach in mild cognitive impairment due to Alzheimer’s disease,” she told us.

MNT also spoke with Scott Kaiser, MD, a board-certified geriatrician and Director of Geriatric Cognitive Health for the Pacific Neuroscience Institute at Providence Saint John’s Health Center in Santa Monica, CA, about this study, who said he found it very encouraging and promising.

“Worldwide dementia cases will triple by 2050 to over 150 million people, so we need to start thinking now and on a massive scale about the best possible strategies and approaches to prevent and treat Alzheimer’s disease, cognitive impairment, and dementia,” Kaiser explained.

“And what’s interesting about this study [and], I think, what’s most promising, is a future in which we have multiple treatments, or an array of treatments, that are addressing a range of underlying mechanisms. […] [W]e have FDA-approved treatments for targeting amyloid plaques, for example, and now here we have a potential treatment targeting a different type of mechanism,” he told us.

“You could envision a future where Alzheimer’s disease is treated much more like a chronic condition like diabetes or hypertension, where you have, again, this wide armamentarium of potential approaches addressing different underlying mechanisms for an overall effective treatment,” he added.

Kaiser commented that he also found it really interesting that this was a study where researchers are repurposing an existing drug, albeit at a lower dose.

“The authors note that it was really the foundation of preclinical research that enabled them to think about this as a potential pathway and a potential treatment target,” he continued.

“It’s important because you think about the value, the importance of research for new drugs and therapies — we need that so desperately […] but at the same time, we also need to keep investing and doubling down in even the preclinical research, the basic fundamental biological understanding of this disease, so that we can identify and better understand these so that we can better understand these underlying pathways and better identify additional and more robust treatment targets.”

– Scott Kaiser, MD