Latrepirdine for Alzheimers disease: Trials and tribulations
Robust preclinical in vitro and in vivo data indicate that latrepirdine has a protective effect against neurotoxic changes, increasing the survival of neurons, inhibiting mitochondrial permeability and reducing mitochondrial instability. The drug has been shown to increase neurite outgrowth, cortical neuron process and branch length and mitochondrial concentration. Nevertheless, a clearly defined mechanism of action has yet to be defined. Speculation regarding its mechanism of action include a preservative effect on mitochondria resulting in neural preservation and it appears to be unrelated to inhibition of acetylcholinesterases and N-methyl-D-aspartic acid-receptor antagonism. Phase I-III studies show demonstrable safety and minimal toxicity in subjects treated with latrepirdine. A Phase II study demonstrated statistically significant cognitive and behavioral improvement in the treatment group and cognitive and behavioral decline from baseline in the placebo group in Russian Alzheimers disease subjects. However, the Phase III monotherapy multinational study failed to reproduce a robust clinical efficacy signal. The reasons for treatment failure are most likely due to the placebo group failing to decline as expected, the proposed mechanism of action maybe not having an effect on the Alzheimers disease process and the data in Phase II being incongruous owing to significant disparities in the populations recruited in the Phase II compared with the Phase III trial. © 2010 Future Medicine Ltd.
Digital Object Identifier (DOI)
Sabbagh, Marwan N. and Berk, Camryn, "Latrepirdine for Alzheimers disease: Trials and tribulations" (2010). Neurology. 925.