Assessment of Efficacy and Safety of Zagotenemab: Results From PERISCOPE-ALZ, a Phase 2 Study in Early Symptomatic Alzheimer Disease

Abstract

Background and objectives: Zagotenemab (LY3303560), a monoclonal antibody that preferentially targets misfolded, extracellular, aggregated tau, was assessed in the PERISCOPE-ALZ phase 2 study to determine its ability to slow cognitive and functional decline relative to placebo in early symptomatic Alzheimer disease (AD).

Methods: Participants were enrolled across 56 sites in North America and Japan. Key eligibility criteria included age of 60-85 years, Mini-Mental State Examination score of 20-28, and intermediate levels of brain tau on PET imaging. In this double-blind study, participants were equally randomized to 1,400 mg or 5,600 mg of zagotenemab, or placebo (IV infusion every 4 weeks for 100 weeks). The primary outcome was change on the Integrated AD Rating Scale (iADRS) assessed by a Bayesian Disease Progression model. Secondary measures include mixed model repeated measures analysis of additional cognitive and functional endpoints as well as biomarkers of AD pathology.

Results: A total of 360 participants (mean age = 75.4 years; female = 52.8%) were randomized, and 218 completed the treatment period. Demographics and baseline characteristics were reasonably balanced among arms. The mean disease progression ratio (proportional decline in the treated vs placebo group) with 95% credible intervals for the iADRS was 1.10 (0.959-1.265) for the zagotenemab low-dose group and 1.05 (0.907-1.209) for the high-dose, where a ratio less than 1 favors the treatment group. Secondary clinical endpoint measures failed to show a drug-placebo difference in favor of zagotenemab. No treatment effect was demonstrated by flortaucipir PET, volumetric MRI, or neurofilament light chain (NfL) analyses. A dose-related increase in plasma phosphorylated tau181 and total tau was demonstrated. Zagotenemab treatment groups reported a higher incidence of adverse events (AEs) (85.1%) compared with the placebo group (74.6%). This difference was not attributable to any specific AE or category of AEs.

Discussion: In participants with early symptomatic AD, zagotenemab failed to achieve significant slowing of clinical disease progression compared with placebo. Imaging biomarker and plasma NfL findings did not show evidence of pharmacodynamic activity or disease modification.

Trial registration information: ClinicalTrials.gov: NCT03518073.

Classification of evidence: This study provides Class II evidence that for patients with early symptomatic AD, zagotenemab does not slow clinical disease progression.

Figure 1. Participant Flow for the PERISCOPE-ALZ Trial

N = number of patients in the treatment arm; n = number of patients in the subgroup.

Figure 2. Percent Slowing of Disease Progression with Zagotenemab

% slowing = (1 − DPR) × 100, where DPR = percent change of the treatment group/percent change of the placebo group. Posterior mean change from baseline and 95% credible intervals were derived using the Bayesian disease progression model. ADAS-Cog = Alzheimer's Disease Assessment Scale; ADCS-iADL = Alzheimer's Disease Cooperative Study–Instrumental Activities of Daily Living Inventory; CDR-SB = Clinical Dementia Rating–Sum of the Boxes; iADRS = Integrated Alzheimer's Disease Rating Scale; MMSE = Mini-Mental State Examination. Note: Study success predefined as 25% slowing on iADRS (bold = primary endpoint).

Figure 3. LS Mean Change of Clinical Assessments From Baseline Based on MMRM Analysis

ADAS-Cog = Alzheimer's Disease Assessment Scale; ADCS-iADL = Alzheimer's Disease Cooperative Study–Instrumental Activities of Daily Living Inventory; CDR-SB = Clinical Dementia Rating–Sum of the Boxes; iADRS = Integrated Alzheimer's Disease Rating Scale; LS = least squares; MMSE = Mini-Mental State Examination. *Unadjusted, 2-sided p value = 0.04 vs placebo.

Figure 4. LS Mean Change of (A) Aggregated Tau Deposition (SUVR) as Determined by Flortaucipir PET and (B) Plasma Biomarkers From Baseline Based on MMRM Analysis

LS = least squares; NfL = neurofilament light; p-tau = phosphorylated tau; SE = standard error; SUVR = standardized uptake value ratio; Wk = week. Note: Modified cerebellar grey used as a reference region.