EADING THEORIES ON THE PATHOphysiology of Alzheimer disease (AD) implicate overproduction of amyloid-␤ (A␤), particularly 42 amino acid peptide A␤ 42 . [1][2][3] Compounds modulating ␥-secretase enzyme cleaving ␤-amyloid precursor protein (APP) to release various forms of A␤ are candidates for treatment of AD. One such compound is tarenflurbil (formerly R-flurbiprofen), a selective A␤ 42lowering agent that has been shown in vitro and in vivo to modulate ␥secretase activity and reduce A␤ 42 production in favor of shorter less toxic forms of A␤ (eg, A␤ 38 and A␤ 37 ). 4,5 In mouse models of AD, tarenflurbil prevents learning and memory deficits and reduces A␤ 42 brain concentrations. 4,6 A phase 2 trial of tarenflurbil suggested that patients with mild AD and moderate AD responded differently to treatment, that patients with mild AD had a dose-related slower rate of decline than those treated with placebo, and that the drug was well tolerated with few adverse effects. 7 On the basis of these results, a large phase 3, randomized, placebo-controlled trial of tarenflurbil was conducted in patients with mild AD. METHODS Study DesignA randomized, double-blind, 2-group parallel study was conducted to com-pare tarenflurbil with placebo for 18 months involving 133 participating trial sites. Written informed consent was obtained from participants, their legally authorized representatives, or both. The See also pp 2565 and 2593.

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To evaluate the safety and tolerability and pharmacokinetic properties of R-flurbiprofen (Tarenflurbil) in normal elderly individuals and to determine the effect of the drug on amyloid beta 42 (Abeta42) levels, we conducted a double-blind, placebo-controlled study of 48 healthy subjects aged 55 to 80. Three successive cohorts were randomized to doses of 400, 800, or 1600 mg/d, or placebo, given as 2 divided doses for 21 days. Blood and cerebrospinal fluid were collected for pharmacokinetic studies and measurement of Abeta levels at baseline and on day 21. R-flurbiprofen was well-tolerated at all 3 doses. The compound penetrated the blood-brain barrier in a dose-dependent manner. From baseline to 21 days, comparisons between study groups revealed no significant differences in changes of cerebrospinal fluid Abeta42 levels and no significant differences in changes of plasma Abeta42 levels at the time of trough drug level at 21 days of treatment. Further analysis of drug concentration-response for plasma samples showed that at the time of peak plasma concentration, higher plasma drug concentration was related to lower Abeta42 plasma levels (P=0.016). R-flurbiprofen had an excellent safety profile and showed dose-dependent central nervous system penetration. Exploratory analyses of plasma Abeta and peak drug levels suggested a short-term effect in plasma that warrants independent verification. The safety, tolerability, and pharmacokinetic profile of R-flurbiprofen in these older individuals support the ongoing studies of this compound in patients with Alzheimer disease.

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