P4‐388: Trailblazer‐alz (Nct03367403): A Phase 2 Disease‐modification Combination Therapy Trial Targeting Multiple Mechanisms of Action Along the Amyloid Pathway

LY3002813 (N3pG) is a humanized IgG1 antibody directed at a truncated N-terminally pyro-glutamate modified amyloid-beta protein (Aβ) epitope specifically localized in amyloid plaques. N3pG was developed to remove existing amyloid plaques through microglial mediated clearance. LY3202626 (BACEi) is a potent oral inhibitor of beta-site amyloid precursor protein-cleaving enzyme 1. N3pG and BACEi combination treatment in APP transgenic mice led to synergistic clearance of amyloid deposits relative to the monotherapies alone. Dual targeting of soluble Aβ (BACE inhibitor) and plaque Aβ (N3pG antibody) is hypothesized to substantially reduce all potentially pathological Aβ species from the brain, achieving maximal target engagement of the amyloid pathway. The ongoing Trailblazer-ALZ study is the first combination therapy trial of potential disease modifying therapies in AD. This study implements the new NIA-AA guidelines for AD classification based on biomarker-defined pathological stage of disease incorporating amyloid PET and tau PET, with a focus on identifying an early symptomatic AD population, achieving high levels of target engagement of the amyloid pathway, and incorporating sensitive clinical outcome measures. Trailblazer-ALZ (NCT03367403) is enrolling 375 participants with early AD by clinical and biomarker criteria into three study arms (in a 1:1:1 ratio) testing double-dummy placebo against monthly intravenous dosing of LY3002813 (N3pG) by itself and in combination with oral daily dosing of LY3202626 (BACEi). Patients are followed for 18 months, with florbetapir F18 PET scans every 6 months. The primary outcome measure is a composite scale of cognition and function – the Integrated Alzheimer's Disease Rating Scale (iADRS). Individualized dosing of LY3002813 is being applied to ensure optimal plaque removal for each patient. The study has >80% power to detect treatment effect assuming active arm having true effect of 50% slowing of iADRS progression compared to placebo. Efficient combination therapy studies can be implemented to maximize target engagement of the amyloid pathway and assess proof of concept in biomarker-defined early AD patients.