Zhao X, Rebeck GW, Hoe HS, Andrews PM.
Tarenflurbil protection from cytotoxicity is associated with an upregulation of neurotrophins.
J Alzheimers Dis. 2008 Nov;15(3):397-407.
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Unfortunately, it is now evident that the doses of tarenflurbil used in the large Phase 3 clinical trials (800 mg b.i.d.) were associated with the typical adverse events of NSAIDs—albeit at a lower rate than with over-the-counter and prescription NSAIDs—and with no evidence whatsoever of any therapeutic effect of tarenflurbil over 18 months [presented at ICAD 2008; see ARF related news story].
The results of this research, that 1-5 microM of tarenflurbil were neuroprotective against Aβ42-induced toxicity and upregulated NGF and BDNF, expand on tarenflurbil’s putative mechanism of action as a γ-secretase modulator that decreases the production of Aβ42.
It is speculative to wonder whether, if this research had been available in the earlier clinical development of tarenflurbil, then would more aggressive Phase 2 dose-finding studies have been undertaken to assess CSF drug concentrations and the possible expression of BDNF as a pharmacodynamic or biomarker of the drugs’ effect? And if so, then would that have influenced the development program?
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