Semorinemab Slowed Cognitive Loss in Alzheimer Disease--The First Positive Clinical Result for an Anti-Tau Antibody

In the 49-week, phase 2 Lauriet trial (NCT03828747), treatment of mild-to-moderate Alzheimer disease (AD) with anti-tau antibody semorinemab (Genentech, South San Francisco CA and AC Immune, Lausanne, Switzerland), slowed cognitive decline by 42.2% (P<.0008) compared with placebo. Analysis of the full modified intention to treat (mITT) group (n=241) showed consistent decrease in cognitive decline across all subgroups, regardless of baseline disease severity, tau load, and genetic status of the apolipoprotein E (ApoE) allele. 

Secondary outcome measures, however, did not show positive results. These included the Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), the Mini-Mental State Examination (MMSE), or the Clinical Dementia Rating-Sum of Boxes (CDR-SB). It was suggested this could reflect a need for longer time on treatment to see such changes or be an issue with the sensitivity of these measurements. It is hoped that the ongoing open-label study and future studies will shed more light on this finding. 

Professor Andrea Pfeifer, chief executive officer of AC Immune SA, commented: “this is the first clinical trial showing a therapeutic benefit for a tau-targeting drug. The 42.2% slowing of cognitive decline was statistically significant and higher than what we have seen in other trials, so we hope semorinemab may be among the breakthroughs leading to current progress in the field. Given that AD is a slowly progressing chronic disease, we look forward to learning about longer-term effects of semorinemab through the ongoing open-label extension being conducted by our partners at Genentech."

Further analyses evaluating semorinemab’s effects on cerebrospinal fluid (CSF) biomarkers are ongoing as is the open-label portion of the study. Tau positron emission tomography (PET) scans did not show changes in nonsoluable tau, and plasma tau levels were significantly increased, suggestive of peripheral binding of soluble tau. 

For the primary endpoint, the mITT population consisted of all individuals who had at least 1 treatment with semorinemab and at least 1 posttreatment assessment with the Alzheimer Disease Assessment Scale-Cognitive 11 (ADAS-Cog11). The slowed cognitive decline observed was primarily due to differences in the memory component of ADAS-Cog11.

Semorinemab treatment was well-tolerated, and adverse events were balanced between placebo and treatment groups. Discontinuation rates were exceptionally low, with only 1 individual leaving the study before the double-blind period ended. 

These data were presented at the Clinical Trials in Alzheimer Disease meeting in Boston, MA November 9-12.