CHF5074 has been shown to inhibit brain β-
amyloid deposition and attenuate
memory deficits in different transgenic mice models of
Alzheimer disease. We evaluated the safety, pharmacokinetics, and pharmacodynamics of 3 ascending dose regimens of
CHF5074 (200, 400, and 600 mg/d for 14 d) in a double-blind, placebo-controlled, parallel group study involving 48 healthy subjects. Plasma, urine, and cerebrospinal fluid (CSF) samples were collected for measuring
drug and main metabolite concentrations and potential
biomarkers of pharmacodynamic activity (β-amyloid1-40, β-amyloid1-42, soluble
CD40 ligand, and
tumor necrosis factor-α). All subjects completed the study, and no serious or severe adverse events were reported. The maximum tolerated dose was close to 600 mg/d with mild
diarrhea being the most frequent adverse event at this dose.
CHF5074 reached peak plasma levels 2 to 3 hours after
drug administration and then was slowly eliminated (t(1/2z)=30 h) in the urine as glucoronide. Systemic exposure to the
drug appeared to be dose-proportional with a 2-fold accumulation ratio at steady state. Metabolite plasma levels peaked at 4 to 5 hours and accounted for about 25% of the parent compound.
Drug levels in the CSF were dose-proportional. The
drug dose-dependently lowered the levels of the soluble
CD40 ligand, a marker of microglia activation, in both plasma and CSF samples.