Abstract
Background: Tarenflurbil is a Selective Aβ42-Lowering Agent (SALA) that modulates γ-secretase activity to preferentially reduce production of Aβ42 in vivo and in vitro. Evidence for potential benefit of tarenflurbil 800 mg bid in subjects with mild AD was recently observed in a randomized, double-blind Phase 2 trial of up to 24 months of treatment. Methods: A target of 1600 subjects with mild AD (MMSE score 20–26) were to be randomized (1:1) to receive tarenflurbil 800 mg bid or placebo for 18 months. Randomization was stratified according to stable use/nonuse of acetylcholinesterase inhibitors (AChEIs) and/or memantine. The co-primary efficacy outcomes are the rate of change (slope) in ADAS-cog and the ADCS-ADL, with assessments conducted every 3 months. The secondary outcome is the CDR-sb, with additional exploratory outcomes including the NPI, Quality of Life-AD, and Caregiver Burden Inventory. ECGs are obtained every 3 months, with adverse events monitored throughout the study. Plasma samples are collected every 3 months for pharmacokinetic and exploratory biomarker analyses. Results: This trial enrolled 1684 subjects at 133 sites in the United States. The last patient visit occured in March 2008, with database lock occuring in June of 2008. At enrollment, 33% of subjects were using AChEIs alone (stable for ≥ 6 months), 6% of subjects were using memantine alone (stable for ≥ 3 months), 41% of subjects were using both AChE is and memantine and 19% of subjects were taking no AD therapy. A second Phase 3 trial of similar design, fully enrolled with 840 subjects, is ongoing in the US, Canada and Europe and is expected to be completed in the clinic in October of 2008. Conclusions: This Phase 3 protocol was developed based on Phase 2 trial results. It is powered to evaluate the efficacy of tarenflurbil with respect to the primary outcomes, and to examine its effect both as monotherapy and as add-on therapy with currently marketed AD medications.