All people with dementia with Lewy bodies (DLB) experience increasing problems with cognition. A very common issue is reduced attention, caused by loss of brain cells that release a chemical messenger called acetylcholine. Gait (how a person walks) is also impacted when acetylcholine cells are lost. The root cause is neurodegeneration in a part of the brain called the basal forebrain, where the brain cells that produce acetylcholine reside. Medications developed for Alzheimer’s disease can offer modest improvement for a time, and do not slow down, stop, or reverse the damage.
Neflamapimod is an investigational treatment being studied in DLB, and a recent placebo-controlled Phase 2 study in people with mild to moderate DLB had positive results for safety and tolerability, with signs of improved cognition and movement. Researchers also studied the drug in a mouse model that develops neurodegeneration of basal forebrain acetylcholine cells to better understand how it works in the brain.
The drug inhibits an enzyme (called p38 MAP kinase alpha or p38α) in both people and mice. This enzyme regulates a protein called Rab5 which is linked to neurodegeneration. In the mice, the drug reversed the neurodegenerative process in the basal forebrain, restoring acetylcholine cells. These results offer translational insights into how the drug may work in humans, as increasing acetylcholine can improve cognition and gait. These two studies, when combined, may represent an important breakthrough. “The findings of this integrated study are both substantive and encouraging. Not only was p38α inhibition with neflamapimod shown to rescue degeneration of the brain’s basal forebrain cholinergic system, a process that is prominent in DLB and contributes to its clinical features, but in an exploratory clinical trial of neflamapimod in DLB, neflamapimod was found to have pharmacologic activity and clinical benefit. These results provide the foundation for confirmatory clinical studies in DLB, which, if positive, will meet the urgent need for therapies for this disease.”
“Despite being the second most common type of neurodegenerative dementia, there are no FDA-approved treatments for DLB,” stated Allison Feldman, CEO for the Lewy Body Dementia Association. “Major investments in DLB research are being made by pharmaceutical companies like EIP Pharma which developed neflamapimod, and the National Institute on Aging and National Neurological Disorders and Stroke at the National Institutes of Health. We are excited to see new drugs being developed for and studied in our particularly vulnerable community.”
A confirmatory Phase 2b clinical trial of neflamapimod in DLB is planned. Neflamapimod has been granted Fast Track status as a potential treatment for DLB by the U.S. Food and Drug Administration (FDA).