Introduction: Histaminergic H3 receptors may play a role in modulating cholinergic and monoaminergic neurotransmission.
This Phase II study evaluated the efficacy and safety of GSK239512, a highly potent, brain penetrant H3 receptor
antagonist as monotherapy treatment for subjects with mild-to-moderate probable Alzheimer's disease (AD). Methods:
In this 16-week, double-blind, randomized, parallel group study, 196 currently untreated subjects with mild-tomoderate
AD (Mini Mental State Examination [MMSE] 16-24) received GSK239512 (n=97); or placebo (n=99) administered
orally each morning. After a two-week placebo run-in period GSK239512 was up-titrated over 4 weeks in a flexible
manner (10-20-40-80 microgram [µg]) followed by a 12-week Maintenance Phase. Co-primary efficacy endpoints were
change from baseline in Episodic Memory and Executive Function/Working Memory composite scores from the CogState
neuropsychological test battery (NTB) at Week 16. Results: Compared to placebo, GSK239512 improved Episodic Memory
at Week 16 (Effect Size [ES] =0.35; p=0.0495). No statistically significant differences were observed on other cognitive
domains or on clinical measures including the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADASCog).
GSK239512 treatment was associated with mild to moderate adverse events with headache, dizziness and events related
to sleep disturbances being the most common and more pronounced in the early titration period when subjects were
first being exposed to GSK239512 at the lower 10µg and 20µg doses. There were no clinically relevant changes in other
safety parameters. Conclusion: GSK239512, at doses up to 80µg/day, improved Episodic Memory in patients with mildto-
moderate AD. However, no improvements were observed on Executive Function/Working Memory or other domains
of cognition. No changes were observed on any of the clinical measures included as secondary endpoints (including
ADAS-Cog) indicating that GSK239512 failed to show benefit in this population. GSK239512 had an acceptable safety
and tolerability profile. These findings suggest that H3 antagonists may, at most, have modest and selective effects on
cognitive function in patients with mild-to-moderate AD.