A phase 1 study to evaluate the safety and pharmacokinetics of PQ912, a glutaminyl cyclase inhibitor, in healthy subjects

• Published in: Alzheimer's & dementia : translational research & clinical interventions Vol. 1; no. 3; pp. 182 - 195
• Main Authors: Lues, Inge, Weber, Frank, Meyer, Antje, Bühring, Uli, Hoffmann, Torsten, Kühn-Wache, Kerstin, Manhart, Susanne, Heiser, Ulrich, Pokorny, Rolf, Chiesa, Joseph, Glund, Konrad
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2015; Elsevier
• Subjects: Alzheimer's disease; Amyloid-beta; Cerebrospinal fluid; Glutaminyl cyclase; Neurology; Other; pE-Aβ; Pyroglutamate; QC inhibitor; QC inhibitor; Glutaminyl cyclase; pE-Aβ; Pyroglutamate; Cerebrospinal fluid; Alzheimer's disease; Amyloid-beta
• ISSN: 2352-8737; 2352-8737
• DOI: 10.1016/j.trci.2015.08.002

Abstract Introduction Pyroglutamate-amyloid-β (pE-Aβ) peptides are major components of Aβ-oligomers and Aβ-plaques, which are regarded as key culprits of Alzheimer's disease (AD) pathology. PQ912 is a competitive inhibitor of the enzyme glutaminyl cyclase (QC), essential for the formation of pE-Aβ peptides. Methods A randomized, double-blind, placebo-controlled, single- and multiple-ascending oral dose study investigated the safety, pharmacokinetics, and pharmacodynamics of PQ912 in healthy nonelderly and elderly subjects. Results PQ912 was considered safe and well tolerated with dose-proportional pharmacokinetics up to doses of 200 mg. At higher doses up to 1800 mg, exposure was supraproportional and exposure in elderly subjects was approximately 1.5- to 2.1-fold higher. Exposure in cerebrospinal fluid (CSF) was approximately 20% of the unbound drug in plasma, and both serum and CSF QC activity was inhibited in a dose-related manner. Discussion This first-in-man study of a compound-targeting QC inhibition justifies further development of PQ912 for the treatment of AD.