Expert opinion on pharmacotherapy
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Expert Opin Pharmacother · Dec 2019
Lessons that can be learnt from the failure of verubecestat in Alzheimer's disease.
Introduction: The amyloid-beta (Aβ) cascade hypothesis is that reducing Aβ levels in the brain will be beneficial in treating Alzheimer's disease. Aβ is formed by the cleavage of amyloid precursor protein by β-site amyloid precure protein cleaving enzyme (BACE1) and the BACE1 inhibitor verubecestat was developed to lower the brain levels of Aβ. However, in the EPOCH trial of verubecestat in mild-to-moderate Alzheimer's disease, it was not beneficial and increased adverse effects. ⋯ Expert opinion: In recruiting subjects to clinical trials in Alzheimer's disease, a clinical diagnosis involving the measurement of Aβ should be undertaken for all subjects, as this may help to clarify the findings. In my opinion, the failure of verubecestat in EPOCH and APECS probably could have been avoided if a safety and potential efficacy trial (phase 2) had been completed prior to starting phase 3. It seems to me that, as we have a poor understanding of the underlying mechanisms/cause of Alzheimer's disease, this is where the research emphasis should be, not phase 3 clinical trials.