The drug dimebon significantly improves the clinical course of Alzheimer's disease (AD) patients with mild-to-moderate disease, conclude authors of an Article published in this week's Dementia Special Edition of The Lancet. Further, dimebon demonstrates increasing benefits over 12 months, which is especially important as no currently approved therapies for AD do this.
Dimebon is an orally-taken drug previously approved in Russia as an antihistamine, which was eventually removed from the market for commercial reasons when later generation antihistamines became available. Dimebon is not currently marketed anywhere. It was subsequently restudied for its ability to block other neurological pathways -- the N-methyl-D-aspartate receptor signalling pathway and cholinesterase -- important in neurodegenerative diseases, although they are no longer thought to be the important mechanisms of dimebon action. More recently, dimebon has shown neuroprotective effects in models for AD and Huntington's disease. Dr Rachelle S Doody, Alzheimer's Disease and Memory Disorders Center, Baylor College of Medicine, Houston, TX, USA, and colleagues did a randomised controlled trial to test the safety, tolerability and efficacy of dimebon in the treatment of patients with mild-to-moderate AD.
The trial enrolled 183 patients at 11 sites in Russia, each with mild-to-moderate AD, determined by the patient having a score on the mini-mental state examination (MMSE) of 10-24. Patients were randomised to dimebon 20mg three times a day (89 patients) or placebo (94). No other antidementia drugs were allowed. Patients were assessed over six months using the Alzheimer's disease cognitive assessment scale (ADAS-cog) and four other secondary measures. 155 (85%) patients (78 (88%) dimebon and 77 (82%) placebo) completed the double-blind study. After the six months, 134 patients entered the subsequent 6-month blinded part of the study, in which they stayed on dimebon or placebo, but neither patients nor investigators knew which treatment patients were taking; 120 patients completed this extension phase.
The researchers found that treatment with dimebon gave significant improvements in ADAS-cog compared with placebo, with a mean difference of four points on the scale between the two groups. The ADAS-cog is a battery of questions that assesses a patient's ability to track dates, ability to understand instructions, follow commands, memorize a list of words, and perform simple tasks such as copying drawings or addressing an envelope. The benefits seen reflected both significant improvement compared with baseline (1.9 points on ADAS-cog) for patients given dimebon, as well as significant decline in those who received placebo. The benefit at the end of the extension study had increased to 6.9 points on ADAS-cog. Dry mouth and depression were the most common adverse events related to dimebon, but proportions of other adverse events were similar in the two groups.
The authors conclude: "[Our] study of patients with mild-to-moderate Alzheimer's disease has shown that patients given dimebon were significantly improved compared with baseline, and compared with those taking placebo, for all five outcome measures. These outcome measures included assessment of cognition, function, and behaviour...The continued and increasing benefit of dimebon over the course of this study is especially important because at present no approved therapies for mild-to-moderate Alzheimer's disease have shown increasing improvement over 12 months."
In an accompanying Comment, Professor Alistair Burns, Psychiatry Research Group, University of Manchester, UK, and Professor Robin Jacoby, Department of Psychiatry, University of Oxford, UK, say: "Addition of treatment options is good news for patients and clinicians -- it promotes choice and offers the possibility of bespoke treatment packages which maximise the chances of response. Doody and colleagues' trial shows that dimebon is better than placebo -- which is no mean feat considering the positive placebo responses in dementia. Further work will establish its efficacy (or otherwise) in addition to, or compared with, established treatments, and indeed a second phase III trial has recently been announced."
Notes to editors: see fig 5, p212 full paper
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