Dementia with Lewy bodies (DLB) is the second most common cause of neurodegenerative dementia after Alzheimer’s disease (AD). DLB is a more rapidly progressive disease than AD, with a median time from diagnosis to death or nursing home admission that is half that seen in AD and is associated with extensive burden on both patients and family caregivers. There is a great unmet medical need, with no approved treatments, only AD and Parkinson’s disease (PD) drugs used off-label to partially or temporarily relieve some of its severe cognitive and motor symptoms. The proposed treatment, neflamapimod, an orally bioavailable, highly specific inhibitor of the intracellular enzyme p38 mitogen activated protein kinase alpha (p38α), is in clinical development by EIP Pharma with a phase 2a study in DLB and phase 2 studies in early AD already completed. Preclinical data indicate that neflamapimod, through inhibiting p38α, therapeutically targets specific pathogenic mechanisms underlying dysfunction and degeneration of neurons in a part of the brain called the basal forebrain, abnormalities in which are considered to be the major pathogenic drivers of the dementia in DLB. For example, neflamapimod increased the number of functioning basal forebrain cholinergic neurons in Ts2 transgenic mice that, along with modeling Down syndrome, develop neurodegeneration in the basal forebrain cholinergic system. Together, such evidence provides a strong scientific rationale for neflamapimod as a disease modifying treatment for DLB. In accordance with this, neflamapimod received Fast-Track designation by the FDA for DLB. A recently completed phase 2a exploratory (i.e., hypothesis-generating) clinical trial (NCT04001517) in 91 patients with mild-to-moderate DLB, also receiving cholinesterase inhibitor therapy, provided preliminary evidence of clinical efficacy of neflamapimod on various cognitive, motor, and functional aspects of the disease. The proposed phase 2b trial will confirm and expand upon these results. The Specific Aims are to, in the context of performing a phase 2b randomized, double- blind, placebo-controlled, 16-week treatment study of neflamapimod (40mg TID) in 160 subjects with mild-to-moderate DLB: (Aim 1). Demonstrate that neflamapimod improves cognition and function, based on primary (Neuropsychological Test Battery) and secondary (Clinical Dementia Rating Scale sum of boxes, Timed Up and Go test, The Alzheimer’s Disease Cooperative Study – Clinical Global Impression of Change) efficacy measures in patients with mild-to-moderate DLB receiving cholinesterase inhibitors; (Aim 2). Assess neuropsychiatric outcomes and safety/tolerability during treatment with neflamapimod in patients with DLB; and (Aim 3). Assess effects of neflamapimod on electroencephalographic (EEG) measures of DLB, specifically beta functional connectivity and alpha-reactivity; both markers of basal forebrain cholinergic dysfunction. Successful completion of this phase 2b trial will inform ...