Background: N-terminally truncated and pyroglutamate (pE)-modified Abeta peptides appear to be an important mediator of the Abeta-dependent cytotoxicity occurring in AD. In vivo, the formation of pE-Abeta 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. Methods: 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. Results: 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. Conclusions: These results justify the further development of PQ912 for the treatment of AD.
Black, R., Lues, I., Weber, F., Meyer, A., Hoffman, T., Pokorny, R., … Glund, K. (2013). P1-333: Safety, pharmacokinetics and pharmacodynamics of PQ912, the first glutaminyl cyclase (QC) inhibitor to treat Alzheimer’s disease, in healthy elderly. Alzheimer’s & Dementia, 9, P280–P280. https://doi.org/10.1016/j.jalz.2013.05.559