AbstractBackgroundNE3107 (3α‐ethynyl‐androst‐5‐ene‐3β,7β,17β‐triol), shows safety, antiinflammatory and insulin‐sensitizing activities in vitro, in animals, and humans. NE3107 binds ERK1/2 and inhibits inflammatory, but not homeostatic NFkB/ERK signaling in vitro, in animals and in humans. NE3107 is blood‐brain permeable, and does not affect neurotransmitter receptors. NE3107 inhibits TNFα‐stimulated NFκB transcription in human macrophages. It also inhibits NFκB nuclear translocation and LPS‐stimulated inflammatory signal transduction. NE3107 prevented IκBα proteolysis in murine macrophages. NE3107 decreased EAE optic nerve microglia, and increased nuclear NFκB in collicular and retinal neurons (homeostatic), but decreased optic nerve head glial nuclear NFκB (inflammatory) in a glaucoma model. NE3107 preserved dopaminergic neurons in MPTP‐treated mice and marmosets. In obese impaired glucose tolerance (IGT) humans, NE3107 decreased CRP, which is involved in AD inflammation and tissue damage, and increased antiinflammatory HDL, which decreases risk of AD pathogenesis. NE3107 increased adiponectin, which suppresses insulin resistance, inflammation, and AD pathology. In obese, inflamed IGT and type 2 diabetes (T2D) subjects, NE3107 decreased insulin resistance, which drives neurodegeneration and AD. Importantly, in obese inflamed T2D subjects, NE3107 decreased inflammation‐driven systems deregulation, known to contribute to AD progression.MethodSafety and activity data from preclinical, toxicology, human clinical trials, and a protocol synopsis for a pivotal trial in AD were submitted, and the FDA allowed NeurMedix to proceed with the NM101 trial.ResultA Phase 3, Double Blind, Randomized, Placebo Controlled, Parallel Group, Multicenter Study of NE3107 in Subjects Who Have Mild to Moderate Alzheimer's Disease (NCT04669028) will evaluate safety and efficacy of oral 20 mg BID NE3107 vs. placebo in 316 subjects with mild to moderate AD. Two coprimary outcome measures ADAS Cog12 and ADCS CGIC will be evaluated as the change from Baseline to Week 30. Secondary endpoints include measures of neuropsychological deficits, functional performance, glycemic control and resource utilization. A subset of patients may volunteer for exploratory vMRI and FDG‐PET scans at baseline and week 30.ConclusionInflammation and insulin resistance drive AD. NE3107 decreases these insults that drive systems dysregulation in AD. This trial is well‐positioned to examine the effects of NE3107 on progression of AD dementia, affecting more than 40 million people globally.