A phase 1 study to evaluate the safety and pharmacokinetics of PQ912, a glutaminyl cyclase inhibitor, in healthy subjects
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...
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| Published in | Alzheimer's & dementia : translational research & clinical interventions Vol. 1; no. 3; pp. 182 - 195 |
|---|---|
| Main Authors | , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Elsevier Inc
01.11.2015
Elsevier |
| Subjects | |
| Online Access | Get full text |
| ISSN | 2352-8737 2352-8737 |
| DOI | 10.1016/j.trci.2015.08.002 |
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| Abstract | 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. |
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| AbstractList | 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. 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. 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. 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. This first-in-man study of a compound-targeting QC inhibition justifies further development of PQ912 for the treatment of AD. 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. 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.INTRODUCTIONPyroglutamate-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.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.METHODSA 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.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.RESULTSPQ912 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.This first-in-man study of a compound-targeting QC inhibition justifies further development of PQ912 for the treatment of AD.DISCUSSIONThis first-in-man study of a compound-targeting QC inhibition justifies further development of PQ912 for the treatment of AD. |
| Author | Bühring, Uli Weber, Frank Hoffmann, Torsten Pokorny, Rolf Heiser, Ulrich Kühn-Wache, Kerstin Meyer, Antje Glund, Konrad Lues, Inge Manhart, Susanne Chiesa, Joseph |
| AuthorAffiliation | b Covance Clinical Research Unit AG, Allschwil (Basel), Switzerland c Covance Clinical Research Unit Ltd, Leeds, UK a Probiodrug AG, Halle (Saale), Germany |
| AuthorAffiliation_xml | – name: c Covance Clinical Research Unit Ltd, Leeds, UK – name: a Probiodrug AG, Halle (Saale), Germany – name: b Covance Clinical Research Unit AG, Allschwil (Basel), Switzerland |
| Author_xml | – sequence: 1 fullname: Lues, Inge – sequence: 2 fullname: Weber, Frank – sequence: 3 fullname: Meyer, Antje – sequence: 4 fullname: Bühring, Uli – sequence: 5 fullname: Hoffmann, Torsten – sequence: 6 fullname: Kühn-Wache, Kerstin – sequence: 7 fullname: Manhart, Susanne – sequence: 8 fullname: Heiser, Ulrich – sequence: 9 fullname: Pokorny, Rolf – sequence: 10 fullname: Chiesa, Joseph – sequence: 11 fullname: Glund, Konrad |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/29854937$$D View this record in MEDLINE/PubMed |
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| Copyright | Probiodrug AG, Germany 2015 Probiodrug AG, Germany 2015 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association. 2015 Probiodrug AG, Germany 2015 |
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| Keywords | QC inhibitor Glutaminyl cyclase pE-Aβ Pyroglutamate Cerebrospinal fluid Alzheimer's disease Amyloid-beta |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Present address: Covance Ltd, Osprey House, Westacott Way, Maidenhead, SL6 3QH, UK. Present address: Serumwerk Bernburg AG, D-06406 Bernburg, Germany. Present address: St. Annaweg 28, CH-4112 Flüh, Switzerland. |
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| Snippet | Abstract Introduction Pyroglutamate-amyloid-β (pE-Aβ) peptides are major components of Aβ-oligomers and Aβ-plaques, which are regarded as key culprits of... 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)... 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... |
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| SubjectTerms | Alzheimer's disease Amyloid-beta Cerebrospinal fluid Glutaminyl cyclase Neurology Other pE-Aβ Pyroglutamate QC inhibitor |
| Title | A phase 1 study to evaluate the safety and pharmacokinetics of PQ912, a glutaminyl cyclase inhibitor, in healthy subjects |
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