Why Did Tarenflurbil Fail in Alzheimer's Disease?

Abstract

There has been a lot of disappointment surrounding the recent failure of the largest ever study in patients with Alzheimer's disease (AD) with tarenflurbil, a compound believed to modulate the activity of γ-secretase, the pivotal enzyme that generates the amyloid-β (Aβ) peptide from the amyloid-β protein precursor. What are the reasons for this setback after the previous apparently encouraging results in a Phase II study? A straightforward explanation of this failure is that the γ-secretase is not the right target for therapy or that, in general, blocking Aβ does not produce clinical benefits in AD. If one still accepts a physiopathological role of Aβ in AD, tarenflurbil could not be the right compound because of its weak pharmacological activity as an Aβ_1-42 lowering agent and its poor brain penetration. In addition, based on previous negative results with several anti-inflammatory drugs in AD, it is hypothesized that the residual anti-inflammatory activity of tarenflurbil may have a detrimental effect on disease progression.