Leveraging Recent Advances in Plasma Biomarkers to Optimize Early Proof of Concept Trials in Alzheimer's Disease.

INTRODUCTION:The importance of biomarkers as a primary outcome or as supportive evidence of clinical effect is rising as the field shifts toward disease-modifying treatments and earlier intervention, because they have lower variability and can indicate disease progression earlier than clinical outcomes. This study assessed the performance of plasma pTau 181 and 217 as a predictive biomarker and potential primary endpoint in early-phase Alzheimer's disease (AD) trials. METHODS:Summary data from recent monoclonal antibody (mAb) trials including plasma pTau 181 and 217 were analyzed to evaluate associations between plasma pTau 181/217 and clinical outcomes. The suitability of plasma pTau 181/217 as a surrogate endpoint for internal decision making was assessed using Prentice criteria. Simulations were conducted to explore the statistical power of using plasma pTau 181/217 as a primary outcome in dose-escalation, proof-of-concept (POC) trial designs. Additional criteria for biomarker validation were applied to simulated data. RESULTS:A strong group-level correlation (r = 0.781) was observed between treatment effects on plasma pTau 181/217 and Clinical Dementia Rating scale - Sum of Boxes (CDR-SB). Mean change in plasma pTau 181/217 significantly predicted mean change in CDR-SB (p = 0.013). The treatment effect on pTau 181/217 was ∼2.6 times greater than on CDR-SB. Prentice Criteria 1, 2, and 4 were met or reasonably met; Criterion 3 is not applicable in the POC setting. CONCLUSION:Plasma pTau 181/217 at 6 months shows future promise to reasonably likely predict clinical benefit for drugs that reduce pTau 181/217 levels, supporting its use as a primary endpoint in early-phase trials. With effect sizes similar to those seen with donanemab, adequately powered trials may require as few as 100 participants. Such trials should include prespecified analyses to evaluate individual-level Prentice criteria, and pTau 181/217 results can be used to predict potential Phase 3 clinical outcomes. Highlights:The group-level correlation between a biomarker treatment effect and clinical endpoint treatment effect is a measurement of the biomarker's ability to predict clinical outcome.The correlation of group level plasma pT217 or pT181 effect size at 6 months with clinical outcome Clinical Dementia Rating scale - Sum of Boxes (CDR-SB) effect size at 12 months was approximately 0.781 with p values of 0.013.Cohen's d effect size of plasma pTau as an outcome was 2.6 times greater than the Cohen's d of CDR-SB, leading to higher power or lower sample sizes.As a primary endpoint, plasma pTau meets or reasonably meets Prentice Criteria 1, 2, and 4, while Criterion 3 was deemed not applicable in the proof-of-concept study setting.