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

Abstract

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.

Figure 1. Participant Flow Diagram

*Two participants who were originally assigned to placebo received semorinemab. OLE = open-label extension.

Figure 2. Mixed-Models for Repeated Measures-Adjusted Change From Baseline in the Placebo and Semorinemab Treatment Arms, for the Coprimary and Secondary Efficacy Endpoints

Coprimary efficacy endpoints: (A) ADAS-Cog11 and (B) ADCS-ADL. Secondary efficacy endpoints: (C) CDR-SB and (D) MMSE. Error bars represent 95% CIs. *p < 0.05, *** p < 0.001. In all other time points, the differences observed were not statistically significant. Weeks 0, 25, 37, and 49 time points include participants from cohort 1 and cohort 2, while week 61 time point includes only participants from cohort 2 (shown separate from cohort 1 and cohort 2 analyses). The numbers of participants in each dose arm assessed at each time point on each outcome measure are shown in the data beneath each graph. ADCS-ADL = Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale; ADAS-Cog-11 = Alzheimer's Disease Assessment Scale-Cognitive Subscale; CDR-SB = Clinical Dementia Rating-Sum of Boxes; MMSE = Mini-Mental State Examination.

Figure 3. (A) Plasma Total Tau and (B) CSF Tau Indices

Error bars represent 95% CIs. **p < 0.05.