Novel use of tau imaging to enrich for pathological homogeneity within the PERISCOPE‐ALZ study of zagotenemab

Abstract Background Zagotenemab (LY3303560), a humanized monoclonal antibody targeting extracellular aggregated tau, is currently in development as a potential disease modifying treatment for early symptomatic Alzheimer’s disease (AD). The PERISCOPE‐ALZ study (Phase 2, NCT03518073) of zagotenemab implements tau PET for classifying AD pathological stage based on the NIA‐AA guidelines (Jack CR, Jr., Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018;14(4):535‐62) and serves as a key eligibility criterion. Here we summarize the study’s screening and baseline characteristics. Method Screening procedures were performed at 60 sites in the United States, Canada, and Japan. Key eligibility criteria include age of 60‐85 years, Mini‐Mental State Exam (MMSE) score of 20‐28, and pre‐defined baseline tau load as assessed by flortaucipir F18 PET. This eligibility strategy was intended to exclude participants with minimal tau burden whose pathology may not be consistent with AD in absence of amyloid pathology confirmation and who are expected to have slower clinical progression. Participants with high tau levels, hypothesized to be less likely to respond to therapy, were also excluded. Result The most common reasons for screen failure were out of range baseline tau levels and cognitive screener score. Of screened participants who underwent a flortaucipir scan, 58% did not meet scan eligibility criteria. Seventy‐nine percent of the flortaucipir scans not meeting eligibility criteria were below pre‐defined tau levels required for inclusion. A higher proportion of females than males who were ineligible based on the tau scan harbored too high of tau levels for eligibility (27% v. 14%, chi‐square p=0.0004). The enrolled cohort had an average age at baseline of 75 years and 53% were female. Average MMSE score at baseline of the enrolled cohort was 23.7. Conclusion PERISCOPE‐ALZ successfully implemented flortaucipir PET imaging as the key inclusion criterion to enroll a pathological homogeneous cohort based on level of tau accumulation. As tau‐targeted therapies for AD advance into clinical research, staged tau pathology as eligibility criterion may be useful in phase 2 proof‐of‐concept trials to test disease modifying therapies. Topline trial results are anticipated in late 2021.

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