Dimebon disappointment

One swallow does not make a summer, and one positive clinical trial does not make an Alzheimer's drug. This was the Alzheimer Research Forum's response in March 2010 [1] to the news release by Pfizer Inc. and Medivation Inc. of the much-awaited data from the phase 3 CONNECTION study with dimebon (latrepirdine) [2]. Unfortunately, the trial met neither its co-primary (cognition and global function) nor its secondary efficacy endpoints. This disappointing news increased scepticism about the unusually positive results of the original phase 2 trial carried out in Russia and published in the Lancet in 2008 [3].Dimebon is orally available and was previously approved in Russia as a nonselective antihistamine but withdrawn from the market with the development of more selective compounds [4]. More recent papers described weak inhibition of butyrylcholinesterase, acetylcholinesterase, the N-methyl-D-aspartate receptor signalling pathway and the mitochondrial permeability transition pore opening [4-7]. Together with the demonstration of neuroprotective effects in Alzheimer's disease (AD) and Huntington's disease models, these observations supported the potential of dimebon as a treatment for AD - although the plausibility of dimebon's mechanism of action has been queried [8].In the phase 2 placebo-controlled study in mild-to-moderate AD funded by Medivation Inc., 155 patients (85% of those enrolled) completed the study [3]. Dimebon (20 mg three times daily) was safe and well tolerated, and significantly improved the clinical course of patients [3]; the mean change from baseline scores significantly favoured the drug for all five outcome measures: two measures of cognition (Mini-mental State Examination, and Alzheimer's Disease Assessment Scale cognitive subscale), one measure of activities of daily living (Alzheimer's Disease Cooperative Study activities of daily living), one measure of behaviour (Neuropsychiatric Inventory) and a global rating scale (Clinician's Interview-bas