Why did tarenflurbil fail in Alzheimer's disease?
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 gamma-secretase, the pivotal enzyme that generates the amyloid-beta (A beta) peptide from the amyloid-beta 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 gamma-secretase is not the right target for therapy or that, in general, blocking A beta does not produce clinical benefits in AD. If one still accepts a physiopathological role of A beta in AD, tarenflurbil could not be the right compound because of its weak pharmacological activity as an A beta(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.
Imbimbo
Bruno P
BP
Research & Development Department, Chiesi Farmaceutici, Parma, Italy. b.imbimbo@chiesigroup.com
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000008:administration & dosage* / Q000009:adverse effects; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D005480:Flurbiprofen / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D017211:Treatment Failure
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C505522:tarenflurbil; D005480:Flurbiprofen; D053829:Amyloid Precursor Protein Secretases