Symposia

Introduction: The amyloid hypothesis proposes that Aβ peptides are intimately involved in the etiology of Alzheimer’s disease (AD) via their aggregation to form toxic complexes that lead to neurodegeneration. Aβ is produced via sequential proteolytic cleavage of the parent molecule, amyloid precursor protein, by β-secretase (BACE1) followed by γ-secretase. Inhibition of BACE1 is a potential novel therapeutic strategy for slowing or halting progression of AD by reducing Aβ production. This approach differs from previous anti-amyloid approaches using monoclonal antibodies to clear Aβ. In the first large-scale clinical trial (EPOCH) of a BACE1 inhibitor, verubecestat doses of 12 mg and 40 mg were ineffective at slowing the rate of cognitive or functional decline over 78 weeks in participants with clinically diagnosed mild-to-moderate AD, despite reducing cerebrospinal fluid (CSF) Aβ levels by 63-81% (Egan et al. NEJM 2018;378:1691-1703). One interpretation of these findings is that treatment at the AD dementia stage is too late in the disease process. A second large trial (APECS; clinicaltrials.gov NCT01953601) was initiated in 2013 to evaluate verubecestat in participants with prodromal AD. Eligible participants had subjective memory decline with objective memory impairment and were amyloid positive (determined by amyloid imaging PET scan or CSF tau: Aβ42 ratio) but did not meet criteria for dementia. A decision to terminate the APECS trial was made in February 2018 following a recommendation by the external Data Monitoring Committee, which concluded that it was unlikely that positive benefit/risk could be established if the trial continued to its scheduled completion in 2019. Objectives: The objectives of this symposium are to present key efficacy and safety findings from the APECS trial and to have a panel of experts discuss the findings and implications for future development of BACE1 inhibitors. Results will be unveiled at CTAD. Discussion: The findings from the APECS trial suggest that blocking Aβ production at the prodromal AD stage does not slow clinical progression. Because the deposition of Aβ takes place years before the prodromal stage, it is possible that administration of an antiamyloid agent like verubecestat may be effective if given even earlier in the disease process. An alternative possibility is that the production of Aβ peptides may not play a major causal role in the pathophysiology of AD. Conclusions: Verubecestat was not effective in slowing clinical progression in participants with prodromal AD.