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Phase 1 safety, tolerability, pharmacokinetics and pharmacodynamics results of a long‐acting C‐type natriuretic peptide prodrug, TransCon CNP

AIM: TransCon CNP is a novel prodrug designed to provide sustained release of C‐type natriuretic peptide (CNP) for once‐weekly therapy, addressing the pathology leading to aberrant skeletal development in achondroplasia. This phase 1 trial was initiated to assess the safety, tolerability, pharmacody...

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Autores principales: Breinholt, Vibeke Miller, Mygind, Per Holse, Christoffersen, Eva Dam, Zhang, Ying, Ota, Sho, Will Charlton, R., Viuff, Dorthe
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9796269/
https://www.ncbi.nlm.nih.gov/pubmed/35481707
http://dx.doi.org/10.1111/bcp.15369
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author Breinholt, Vibeke Miller
Mygind, Per Holse
Christoffersen, Eva Dam
Zhang, Ying
Ota, Sho
Will Charlton, R.
Viuff, Dorthe
author_facet Breinholt, Vibeke Miller
Mygind, Per Holse
Christoffersen, Eva Dam
Zhang, Ying
Ota, Sho
Will Charlton, R.
Viuff, Dorthe
author_sort Breinholt, Vibeke Miller
collection PubMed
description AIM: TransCon CNP is a novel prodrug designed to provide sustained release of C‐type natriuretic peptide (CNP) for once‐weekly therapy, addressing the pathology leading to aberrant skeletal development in achondroplasia. This phase 1 trial was initiated to assess the safety, tolerability, pharmacodynamics (PD) and pharmacokinetics (PK) of TransCon CNP. METHODS: This randomized, placebo‐controlled, single‐ascending dose phase 1 trial was performed at two sites in Australia and enrolled 45 healthy adult males. Subjects received placebo or TransCon CNP (single‐ascending dose cohorts [3, 10, 25, 75 or 150 μg CNP/kg]). The primary endpoint was frequency of adverse events and other safety outcomes. Other endpoints included PK and PD measured by cyclic guanosine‐monophosphate (cGMP) and amino‐terminal propeptide of CNP (NTproCNP). RESULTS: TransCon CNP provided continuous systemic exposure to CNP over at least 7 days post‐dose. Plasma and urine levels of cGMP were significantly increased in subjects administered TransCon CNP at 75‐150 μg CNP/kg, indicating target engagement of active CNP at the natriuretic peptide receptor‐B (NPR‐B) for at least 1 week post‐dose. TransCon CNP was well‐tolerated, with no serious treatment‐emergent adverse events or discontinuations. Extensive cardiac safety assessments did not reveal any clinically relevant effects on electrocardiogram parameters, including heart rate, PR, QRS and QTcF intervals. CONCLUSIONS: Safety and PD data from this phase 1 trial support that TransCon CNP is well tolerated, with a PK profile compatible with a once‐weekly dosing regimen. Further studies are ongoing to evaluate the potential of TransCon CNP to positively impact abnormal endochondral ossification in children with achondroplasia.
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spelling pubmed-97962692022-12-30 Phase 1 safety, tolerability, pharmacokinetics and pharmacodynamics results of a long‐acting C‐type natriuretic peptide prodrug, TransCon CNP Breinholt, Vibeke Miller Mygind, Per Holse Christoffersen, Eva Dam Zhang, Ying Ota, Sho Will Charlton, R. Viuff, Dorthe Br J Clin Pharmacol Original Articles AIM: TransCon CNP is a novel prodrug designed to provide sustained release of C‐type natriuretic peptide (CNP) for once‐weekly therapy, addressing the pathology leading to aberrant skeletal development in achondroplasia. This phase 1 trial was initiated to assess the safety, tolerability, pharmacodynamics (PD) and pharmacokinetics (PK) of TransCon CNP. METHODS: This randomized, placebo‐controlled, single‐ascending dose phase 1 trial was performed at two sites in Australia and enrolled 45 healthy adult males. Subjects received placebo or TransCon CNP (single‐ascending dose cohorts [3, 10, 25, 75 or 150 μg CNP/kg]). The primary endpoint was frequency of adverse events and other safety outcomes. Other endpoints included PK and PD measured by cyclic guanosine‐monophosphate (cGMP) and amino‐terminal propeptide of CNP (NTproCNP). RESULTS: TransCon CNP provided continuous systemic exposure to CNP over at least 7 days post‐dose. Plasma and urine levels of cGMP were significantly increased in subjects administered TransCon CNP at 75‐150 μg CNP/kg, indicating target engagement of active CNP at the natriuretic peptide receptor‐B (NPR‐B) for at least 1 week post‐dose. TransCon CNP was well‐tolerated, with no serious treatment‐emergent adverse events or discontinuations. Extensive cardiac safety assessments did not reveal any clinically relevant effects on electrocardiogram parameters, including heart rate, PR, QRS and QTcF intervals. CONCLUSIONS: Safety and PD data from this phase 1 trial support that TransCon CNP is well tolerated, with a PK profile compatible with a once‐weekly dosing regimen. Further studies are ongoing to evaluate the potential of TransCon CNP to positively impact abnormal endochondral ossification in children with achondroplasia. John Wiley and Sons Inc. 2022-06-01 2022-11 /pmc/articles/PMC9796269/ /pubmed/35481707 http://dx.doi.org/10.1111/bcp.15369 Text en © 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Articles
Breinholt, Vibeke Miller
Mygind, Per Holse
Christoffersen, Eva Dam
Zhang, Ying
Ota, Sho
Will Charlton, R.
Viuff, Dorthe
Phase 1 safety, tolerability, pharmacokinetics and pharmacodynamics results of a long‐acting C‐type natriuretic peptide prodrug, TransCon CNP
title Phase 1 safety, tolerability, pharmacokinetics and pharmacodynamics results of a long‐acting C‐type natriuretic peptide prodrug, TransCon CNP
title_full Phase 1 safety, tolerability, pharmacokinetics and pharmacodynamics results of a long‐acting C‐type natriuretic peptide prodrug, TransCon CNP
title_fullStr Phase 1 safety, tolerability, pharmacokinetics and pharmacodynamics results of a long‐acting C‐type natriuretic peptide prodrug, TransCon CNP
title_full_unstemmed Phase 1 safety, tolerability, pharmacokinetics and pharmacodynamics results of a long‐acting C‐type natriuretic peptide prodrug, TransCon CNP
title_short Phase 1 safety, tolerability, pharmacokinetics and pharmacodynamics results of a long‐acting C‐type natriuretic peptide prodrug, TransCon CNP
title_sort phase 1 safety, tolerability, pharmacokinetics and pharmacodynamics results of a long‐acting c‐type natriuretic peptide prodrug, transcon cnp
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9796269/
https://www.ncbi.nlm.nih.gov/pubmed/35481707
http://dx.doi.org/10.1111/bcp.15369
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