Background: The histamine H3 receptor plays a critical role in the negative neuromodulation of neurotransmitters
involved in cognitive function. H3 receptor antagonists/inverse agonists have been shown to exert pro-cognitive effects
in pre-clinical models. GSK239512 is a potent and selective H3 receptor antagonist developed for the treatment of
cognitive dysfunction in neurodegenerative disorders. In this study we examined the safety, tolerability, pharmacokinetics
and pro-cognitive effects of GSK239512 (oral) in patients with mild to moderate Alzheimer’s disease using ascending
dose titration regimens.
Methods: The study was conducted in two parts. Part A was a single-blind, placebo run-in, flexible dose titration over 9
days in two cohorts, each consisting of two patients. Part B was a double-blind, randomised, placebo controlled, parallel
group, which investigated 3 flexible dose titration regimens over 4 weeks in 3 cohorts, each consisting of eight patients.
Results: Overall, the 5/10/20/40μg and 10/20/40/80μg regimens were well-tolerated. The regimen of 20/40/80/150μg
showed the poorest tolerability likely due to the higher starting dose. There were no clinically significant abnormalities in
haematology, clinical chemistry, urinalysis parameters and cardiovascular parameters. GSK239512 had positive effects
on tasks of attention and memory with effect sizes between 0.56 and 1.37.
Conclusions: GSK239512 displayed asatisfactory level of tolerability in patients with Alzheimer’s disease with evidence
for positive effects on attention and memory. The findings suggest that a titration regimen with a starting dose of 5-10μg
and a maximum dose of 80μg is likely to be a well-tolerated and potentially efficacious regimen for future clinical trials
in patients with Alzheimer’s disease. These findings await replication in a larger study.