Central pharmacodynamic activity of solanezumab in mild Alzheimer's disease dementia

INTRODUCTION: Solanezumab treatment was previously shown to significantly increase total (bound + unbound) cerebrospinal fluid (CSF) levels of amyloid β (Aβ)(1–40) and Aβ(1–42) in patients with mild to moderate Alzheimer's disease dementia yet did not produce meaningful cognitive effects. This analysis assessed solanezumab's central nervous system target engagement by evaluating changes in CSF total and free Aβ isoforms and their relationship with solanezumab exposure. METHODS: CSF Aβ isoform concentrations were measured in patients with mild Alzheimer's disease dementia from a pooled EXPEDITION + EXPEDITION2 population and from EXPEDITION3. CSF solanezumab concentrations were determined from EXPEDITION3. RESULTS: Solanezumab produced statistically significant increases in CSF total Aβ isoforms versus placebo, which correlated with CSF solanezumab concentration. Inconsistent effects on free Aβ isoforms were observed. Solanezumab penetration into the central nervous system was low. DISCUSSION: Solanezumab administration engaged the central molecular target, and molar ratio analyses demonstrated that higher exposures may further increase CSF total Aβ concentrations.