NXX-066 in patients with Alzheimer's disease: a bridging study.

Reduced cholinergic transmission is a key neurotransmitter dysfunction in Alzheimer's Disease (AD). NXX-066, a physostigmine analog and acetylcholinesterase (AChE) inhibitor, has demonstrated activity in animal models of memory function, and was well tolerated in healthy subjects up to a single dose of 64 mg and multiple doses of 60 mg QD for seven days. Since AChE inhibitors are often tolerated differently in AD patients than in healthy volunteers, a randomized, placebo-controlled, double-blind, single-center, inpatient bridging study was conducted to determine the maximum tolerated dose (MTD) of NXX-066 in the target patient population. Seven consecutive panels of eight AD patients each (6 active, 2 placebo) received fixed oral doses of NXX-066 (20, 30, 40, 50, 60, 70, or 80 mg BID) for seven days. Initiation of each subsequent panel (dose group) was contingent upon the tolerability of lower dose levels. The MTD was determined to be 70 mg BID when four of six patients receiving 80 mg BID were prematurely discontinued from the study due to nausea and/or vomiting, accompanied in some patients by mild to moderate dizziness, headache, asthenia, and gastric symptoms. Wide variability in plasma levels of NXX-066 was observed in all dose panels. AChE inhibition in whole blood correlated with both maximum plasma concentration and dose; however, AChE inhibition was not predictive of adverse events. In this study, AD patients tolerated larger daily doses of NXX-066 on a BID regimen than healthy normal subjects had tolerated with QD dosing. Further studies are warranted to examine whether differing tolerability between patients and healthy subjects or the reduced dosing interval explains these findings.