Randomized Phase II Study of the Safety and Efficacy of Semorinemab in Participants With Mild-to-Moderate Alzheimer Disease: Lauriet

Abstract

<h3>Background and Objectives</h3> Accumulation of tau pathology in Alzheimer’s disease (AD) correlates with cognitive decline. Anti-tau immunotherapies were proposed as potential interventions in AD. While antibodies targeting N-terminal tau failed to demonstrate clinical efficacy in prodromal-to-mild AD, their utility at other disease stages was not yet evaluated. Lauriet is a phase II study of an anti-tau monoclonal antibody, semorinemab, in patients with mild-to-moderate AD. <h3>Methods</h3> The phase II Lauriet study included a randomized, placebo-controlled, double-blind period, during which participants with mild-to-moderate AD received intravenous semorinemab 4500 mg or placebo every 4 weeks for 48 or 60 weeks. Participants who chose to continue in the subsequent optional open-label extension (OLE) received semorinemab 4500 mg every 4 weeks for up to 96 weeks. Co-primary efficacy endpoints were change from baseline to week 49 or 61 on the 11-item version of the Alzheimer’s disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) and the Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale. Secondary efficacy endpoints included change from baseline on the Mini-Mental Status Examination (MMSE) and Clinical Dementia Rating-Sum of Boxes (CDR-SB). Safety, pharmacokinetics and pharmacodynamic effects were also evaluated. <h3>Results</h3> Between Dec 3, 2018 and Feb 27, 2020, 624 individuals were screened, 272 participants were randomized, and 238 were included in the modified intent-to-treat population [received ≥1 dose(s) of study medication and underwent baseline and ≥1 post-baseline assessment(s)]. Baseline characteristics were well-balanced. At week 49, the semorinemab arm demonstrated a 42.2% reduction (-2.89 points, 95% confidence interval: -4.56 to -1.21, p=0.0008) in decline on ADAS-Cog11 (co-primary endpoint) relative to placebo. However, no treatment effects were observed on the ADCS-ADL (co-primary endpoint; absolute difference between the two treatment arms in ADCS-ADL score change from baseline of -0.83 points, 95% confidence interval: -3.39, 1.72, p=0.52), or on the MMSE or CDR-SB (secondary endpoints). Semorinemab was safe and well-tolerated. <h3>Discussion</h3> Based on the results of the pre-specified co-primary endpoints this study was negative. While semorinemab had a significant effect on cognition measured by ADAS-Cog11, this effect did not extend to improved functional or global outcomes. These results may warrant further exploration of semorinemab or other anti-tau therapies in mild to moderate AD. <h3>Classification of Evidence</h3> This study provides Class I evidence that semorinemab does not slow functional decline in patients with mild-to-moderate AD. <h3>Trial Registration Information</h3> The Lauriet study is registered on ClinicalTrials.gov, NCT03828747 (status: active, not recruiting), and EudraCT 2018-003398-87.