P1-333: Safety, pharmacokinetics and pharmacodynamics of PQ912, the first glutaminyl cyclase (QC) inhibitor to treat Alzheimer's disease, in healthy elderly

N-terminally truncated and pyroglutamate (pE)-modified Aβ peptides appear to be an important mediator of the Aβ-dependent cytotoxicity occurring in AD. In vivo, the formation of pE-Aβ is catalyzed by glutaminyl cyclase (QC), suggesting that inhibition of QC in the brain represents an important new therapeutic target. PQ912 is the first in a series of orally available, small molecule QC inhibitors being developed for the treatment of AD. Following a single and multiple dose administration study in healthy young subjects (Weber et al, AD/PD 2013), this study evaluated the safety, pharmacokinetics and pharmacodynamics of PQ912 in healthy elderly subjects. 16 healthy male and female subjects volunteers between the ages of 65 and 80 were randomized to PQ912 (6/cohort) or placebo (2/cohort), receiving multiple twice daily doses of 200 mg and 300 mg as capsules for 7 days in a single center Phase 1 study. Adverse events, ECG and laboratory analysis were assessed for safety. Pharmacokinetics was measured under fasted conditions in blood and CSF. PQ912 was safe and well tolerated throughout the dose range tested. As in the previously tested non-elderly, the maximum tolerated dose was not reached during this study and PQ912 exposure also increased dose proportionally in the elderly subjects. Compared with the non-elderly subjects, the AUC in the elderly subjects was increased approximately 2-fold at the doses tested, suggesting a reduced first pass effect in elderly. Half-lives in plasma and CSF were essentially the same as in the non-elderly groups. The plasma and CSF drug concentrations were highly correlated and at 300 mg bid mean CSF drug concentration corresponded to an average target occupancy of about 70%, based on an in-vitro K i for QC of 30 nM. These results justify the further development of PQ912 for the treatment of AD.