CYP46A1 Activation By Low-Dose Efavirenz Enhances Brain Cholesterol Metabolism In Subjects With Mild Cognitive Impairment Due To Alzheimer’s Disease

Abstract Background: Efavirenz is an anti-HIV drug, and cytochrome P450 46A1 (CYP46A1) is a CNS-specific enzyme that metabolizes cholesterol to 24-hydroxycholesterol (24HC). We have previously shown that allosteric CYP46A1 activation by low-dose efavirenz in a transgenic mouse model of Alzheimer’s disease (AD) enhanced both cholesterol elimination and turnover in the brain and improved animal performance in memory tests. Here, we sought to determine whether CYP46A1 could be similarly activated by a low-dose efavirenz in human subjects. Methods: This pilot study enrolled 5 subjects with mild cognitive impairment due to AD. Participants were randomized to placebo (n=1) or two daily efavirenz doses (50 mg and 200 mg, n=2 for each) for 20 weeks and evaluated for safety and CYP46A1 target engagement (plasma 24HC levels). A longitudinal mixed model was used to ascertain statistical significance of target engagement. We also measured 24HC in CSF and conducted a unique stable isotope labeling kinetics (SILK) study with deuterated water to directly measure CYP46A1 activity changes in the brain.Results: In all subjects receiving efavirenz, there was a statistically significant increase (P £ 0.001) in the levels of plasma 24HC. The levels of 24HC in the CSF of subjects on the 200 mg-dose of efavirenz were also increased. Target engagement was further supported by the labeling kinetics of 24HC by deuterated water in the SILK study. There were no serious adverse effects in any subjects. Conclusions: Our findings provide evidence of efavirenz target engagement in human subjects with AD. This supports pursuit of a larger trial for further determination and confirmation of the efavirenz dose that exerts maximal enzyme activation, as well as evaluation of this drug effects on AD biomarkers and clinical symptomatology.Trial registration: ClinicalTrials.gov NCT03706885.