VERUBECESTAT DISEASE PROGRESSION MODELING FROM APECS, A PHASE 3 TRIAL IN PRODROMAL ALZHEIMER’S DISEASE: NO DOSE- AND EXPOSURE-DEPENDENCY IN CLINICAL ENDPOINTS

The BACE inhibitor verubecestat (MK-8931) demonstrated cognitive and functional decline relative to placebo in a 2-year Phase 3 trial of individuals with prodromal AD (NCT01953601). Disease progression modeling was used to investigate the temporal pattern of the cognitive and functional deficits and dose- or exposure-dependency in the Results. Disease progression models for the clinical efficacy outcomes (ADAS-cog13, ADAS-cog11, CDR-SB, ADCS-ADL) were developed using a similar Methodology to an established ADAS-cog disease progression model (Ref 1). Parameters describing placebo response were first estimated and fixed based on the published model and using the trial data from the placebo arm. Then Akaike Information Criteria (AIC) were used to select among alternative drug effect models (effects on the underlying progression rate vs an offset with no change in underlying progression rate). The best model was then tested for dose- and exposure-dependency in the drug effect. Models describing the drug effect as a detrimental offset occurring early in therapy without a change in underlying progression rate resulted in a large drop in AIC for ADAS-cog13 (-129), ADAS-cog11 (-105.7), and CDR-SB (-21.9) and a moderate drop in ADCS-ADL (-6.9) indicating a statistically favorable model (