A Systematic Review to Evaluate the Effect of Neflamapimod on Cognitive Function and Progression of Dementia

Treatment options for dementia mainly comprise of symptomatic treatment, as no disease-modifying therapy currently exists that directly reduces the pathology. This systematic review assessed the effectiveness of neflamapimod (VX-745), a p38α kinase inhibitor, as a therapeutic agent for treating dementia, including Alzheimer's disease (AD) and Lewy Body Dementia (LBD). The systematic review evaluated the therapeutic effect of neflamapimod on dementia. Five electronic databases were included in the systematic review: PubMed, Embase, ProQuest, Cochrane Library, and Web of Science, which were searched until May 5, 2024. Two independent reviewers conducted title and abstract screening, followed by full-text review and data extraction, with disagreements resolved by a third reviewer. The risk of bias in the included studies was assessed using the ROB 2.0 tool. PROSPERO Registration ID: CRD42024542377. The review identified clinical results, biomarker effects, and mechanistic insights from two key trials. Due to the inclusion of only two eligible studies with varying methodologies and outcome measures, a meta-analysis could not be performed. While the primary cognitive outcomes, such as "neuropsychological test battery (NTB)" and "Hopkins Verbal Learning Test-Revised (HVLT-R)" were not statistically different, episodic memory, executive function, attention, gait dysfunction, and motor issues showed improvements, especially in patients with elevated plasma tau181, a marker for AD pathology. Biomarker analysis also indicated a statistically significant reduction in cerebrospinal fluid (CSF) tau and phosphorylated tau biomarkers, which are closely related to neuroinflammation and synaptic impairment in dementia. The findings of the current review suggested that while the cognitive effects of neflamapimod remain uncertain, its ability to influence disease-specific biomarkers makes it a potential drug to be used in dementia. This review connects biological and clinical outcomes, paving the way for future advancements in dementia treatment strategies.