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Lues I, Weber F, Meyer A, et al. A phase 1 study to evaluate the safety and pharmacokinetics of PQ912, a glutaminyl cyclase inhibitor, in healthy subjects. Alzheimers Dement (N Y). 2015;1(3):182-195doi: 10.1016/j.trci.2015.08.002.
Lues, I., Weber, F., Meyer, A., Bühring, U., Hoffmann, T., Kühn-Wache, K., Manhart, S., Heiser, U., Pokorny, R., Chiesa, J., & Glund, K. (2015). A phase 1 study to evaluate the safety and pharmacokinetics of PQ912, a glutaminyl cyclase inhibitor, in healthy subjects. Alzheimer's & dementia (New York, N. Y.), 1(3), 182-195. https://doi.org/10.1016/j.trci.2015.08.002
Lues, Inge, et al. "A phase 1 study to evaluate the safety and pharmacokinetics of PQ912, a glutaminyl cyclase inhibitor, in healthy subjects." Alzheimer's & dementia (New York, N. Y.) vol. 1,3 (2015): 182-195. doi: https://doi.org/10.1016/j.trci.2015.08.002
Lues I, Weber F, Meyer A, Bühring U, Hoffmann T, Kühn-Wache K, Manhart S, Heiser U, Pokorny R, Chiesa J, Glund K. A phase 1 study to evaluate the safety and pharmacokinetics of PQ912, a glutaminyl cyclase inhibitor, in healthy subjects. Alzheimers Dement (N Y). 2015 Oct 03;1(3):182-195. doi: 10.1016/j.trci.2015.08.002. eCollection 2015 Nov. PMID: 29854937; PMCID: PMC5975062.
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Alzheimers Dement (N Y). 2015 Oct 03;1(3):182-195. doi: 10.1016/j.trci.2015.08.002. eCollection 2015 Nov.

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

Alzheimer's & dementia (New York, N. Y.)

Inge Lues, Frank Weber, Antje Meyer, Uli Bühring, Torsten Hoffmann, Kerstin Kühn-Wache, Susanne Manhart, Ulrich Heiser, Rolf Pokorny, Joseph Chiesa, Konrad Glund

Affiliations

  1. Probiodrug AG, Halle (Saale), Germany.
  2. Covance Clinical Research Unit AG, Allschwil (Basel), Switzerland.
  3. Covance Clinical Research Unit Ltd, Leeds, UK.

PMID: 29854937 PMCID: PMC5975062 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.

Keywords: Alzheimer's disease; Amyloid-beta; Cerebrospinal fluid; Glutaminyl cyclase; Pyroglutamate; QC inhibitor; pE-Aβ

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