Pharmacodynamic effects of semorinemab on plasma and CSF biomarkers of Alzheimer’s disease pathophysiology

Abstract

INTRODUCTION Semorinemab, an anti-tau monoclonal antibody, was evaluated in two Phase II trials as a disease-modifying treatment for Alzheimer's disease (AD). Plasma and cerebrospinal fluid (CSF) samples were collected from trial participants to evaluate the pharmacodynamic effects of semorinemab and elucidate its mechanism of action. METHODS Qualified immunoassays were used to measure plasma and CSF biomarkers of tau, amyloidosis, glial activity, neuroinflammation, synaptic function, and neurodegeneration from participants enrolled in the Tauriel (NCT03289143) and Lauriet (NCT03828747) Phase II trials in prodromal-to-mild (P2M) and mild-to-moderate (M2M) AD. RESULTS Significant increases in plasma phosphorylated Tau 181 (pTau181) and CSF Chitinase-3-like protein 1 (YKL-40) followed administration of semorinemab in both studies. In the Lauriet study, plasma glial fibrillary protein (GFAP) levels rose progressively over the study period in the placebo group, but remained stable over time with the administration of semorinemab. In contrast, this was not observed in the Tauriel study. Semorinemab had no consistent impact on other biomarkers of AD pathophysiology that were evaluated. DISCUSSION Semorinemab engages and stabilizes plasma pTau181 in a manner consistent with previously reported data [1,2], and levels do not decrease after prolonged drug exposure. Increases to CSF YKL-40 suggest that semorinemab may stimulate microglia activation, while stabilization of plasma GFAP levels in Lauriet participants indicate that semorinemab may moderate reactive gliosis in M2M AD.