[p4–567]: a phase 1 safety trial of the aβ oligomer receptor antagonist ct1812

CT1812 is a first in class therapeutic currently in Phase 1/2 testing in AD patients (ClinicalTrials.gov Identifier: NCT02907567) that selectively displaces Aβ oligomers from synaptic receptor sites and clears them from the brain into the cerebrospinal fluid, restoring cognitive performance to normal in aged transgenic mouse models of AD. In prior clinical studies, CT1812 was safe and well tolerated with multiple doses up to 560 mg in healthy elderly volunteers. CSF concentrations observed with multiple dosing of CT1812 indicate that they exceed the expected minimum target concentrations needed to improve memory in AD patients. To further the clinical development of CT1812 a study was conducted to evaluate potential drug-drug interactions of CT1812 involving effects on cytochrome P450 (CYP) isoenzymes. A Phase 1, single-center, open-label, single-sequence drug-drug interaction study was performed to evaluate the effect CT1812 on the pharmacokinetics of 4 CYP probe drugs (tolbutamide, midazolam, dextromethorphan and omeprazole) given before and following administration of 6 consecutive daily oral doses of 560 mg CT1812 (steady state). Small increases (<2 fold) in dextromethorphan and dextrorphan exposure were observed after co-administration of dextromethorphan with steady-state CT1812, consistent with a weak inhibitory interaction of CT1812 on the CYP2D6 enzyme. Small decreases (<50%) in midazolam exposure were observed after co-administration of midazolam with steady-state CT1812, consistent with weak induction of the CYP3A4 enzyme by CT1812. There were no clinically meaningful interactions between CT1812 and omeprazole (CYP2C19) or tolbutamide (CYP2C9). Based on the weak drug-drug interactions observed in this study between steady-state CT1812 and standard CYP probe drugs, clinically meaningful implications are unlikely. These results permit fewer medication exclusions in AD current and future clinical trials including the planned Phase 2 trial in mild to moderate AD.