AI Summary
The study found that the anti-tau monoclonal antibody, semorinemab, showed a significant effect on cognition but did not improve functional or global outcomes in patients with mild-to-moderate Alzheimer's disease. The results suggest that further exploration of semorinemab or other anti-tau therapies in mild-to-moderate AD may be needed. [Source: Lauriet study on semorinemab in patients with mild-to-moderate AD did not reach primary endpoints]
Background and Objectives
Accumulation of tau pathology in Alzheimer 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 evaluated in prior studies. Lauriet is a phase 2 study of an anti-tau monoclonal antibody, semorinemab, in patients with mild-to-moderate AD.
Methods
The phase 2 Lauriet study included a randomized, placebo-controlled, double-blind period, during which participants with mild-to-moderate AD received 4,500 mg of IV semorinemab or placebo every 4 weeks for 48 or 60 weeks. Participants who chose to continue in the subsequent optional open-label extension received 4,500 mg of semorinemab every 4 weeks for up to 96 weeks. Coprimary 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 State Examination (MMSE) and Clinical Dementia Rating-Sum of Boxes (CDR-SB). Safety, pharmacokinetics, and pharmacodynamic effects were also evaluated.
Results
Between December 3, 2018, and February 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 postbaseline assessment(s)). Baseline characteristics were well balanced. At week 49, the semorinemab arm demonstrated a 42.2% reduction (–2.89 points, 95% CI –4.56 to –1.21, p = 0.0008) in decline on the ADAS-Cog11 (coprimary endpoint) relative to the placebo arm. However, no treatment effects were observed on the ADCS-ADL scale (coprimary endpoint; absolute difference between the 2 treatment arms in the ADCS-ADL score change from baseline of –0.83 points, 95% CI –3.39 to 1.72, p = 0.52) or on the MMSE or CDR-SB (secondary endpoints). Semorinemab was safe and well tolerated.
Discussion
Based on the results of the prespecified coprimary endpoints, this study was negative. While semorinemab had a significant effect on cognition measured by the 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.
Classification of Evidence
This study provides Class I evidence that semorinemab does not slow functional decline in patients with mild-to-moderate AD.
Trial Registration Information
The Lauriet study is registered on ClinicalTrials.gov, NCT03828747, and EudraCT 2018-003398-87.