Drug evaluation: (R)-flurbiprofen--an enantiomer of flurbiprofen for the treatment of Alzheimer's disease

Abstract

(R)-flurbiprofen, the R-enantiomer of racemic flurbiprofen, is undergoing development by Myriad Genetics Inc, under license from Encore Pharmaceuticals Inc, for the potential treatment of Alzheimer's disease (AD). Devoid of any direct cyclooxygenase inhibition, which is associated with the more toxic S-enantiomer of flurbiprofen, (R)-flurbiprofen appears to modulate gamma-secretase, the enzyme that cleaves the C-terminal portion of the malignant Abeta(1-42) peptide out of amyloid precursor protein. In murine models of AD, (R)-flurbiprofen lowered brain levels of Abeta(1-42), and chronic dosing reduced brain amyloid pathology and prevented defects in learning and memory. In a phase II clinical trial in AD, (R)-flurbiprofen was determined to be most effective in a subset of patients who had high blood concentrations of the drug (> 75 microg/ml). These patients demonstrated a benefit in cognitive and behavioral performance that ranged from 36 to 48%, and statistical significance was achieved for two out of three trial endpoints. Compared with placebo, (R)-flurbiprofen also significantly reduced the incidence of psychiatric problems and the average time to a first psychiatric incidence. (R)-flurbiprofen has been generally well tolerated at high doses in clinical trials. Two pivotal phase III clinical trials in AD are underway in more than 2400 patients. The compound had also been under development for the treatment of prostate cancer; however, this indication was discontinued after disappointing phase IIa trial results.