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A Novel NF‐κB Inhibitor, Edasalonexent (CAT‐1004), in Development as a Disease‐Modifying Treatment for Patients With Duchenne Muscular Dystrophy: Phase 1 Safety, Pharmacokinetics, and Pharmacodynamics in Adult Subjects
In Duchenne muscular dystrophy (DMD), NF‐κB is activated in skeletal muscle from infancy regardless of the underlying dystrophin mutation and drives inflammation and muscle degeneration while inhibiting muscle regeneration. Edasalonexent (CAT‐1004) is a bifunctional orally administered small molecul...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5412838/ https://www.ncbi.nlm.nih.gov/pubmed/28074489 http://dx.doi.org/10.1002/jcph.842 |
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author | Donovan, Joanne M. Zimmer, Michael Offman, Elliot Grant, Toni Jirousek, Michael |
author_facet | Donovan, Joanne M. Zimmer, Michael Offman, Elliot Grant, Toni Jirousek, Michael |
author_sort | Donovan, Joanne M. |
collection | PubMed |
description | In Duchenne muscular dystrophy (DMD), NF‐κB is activated in skeletal muscle from infancy regardless of the underlying dystrophin mutation and drives inflammation and muscle degeneration while inhibiting muscle regeneration. Edasalonexent (CAT‐1004) is a bifunctional orally administered small molecule that covalently links 2 compounds known to inhibit NF‐κB, salicylic acid and docosahexaenoic acid (DHA). Edasalonexent is designed to inhibit activated NF‐κB upon intracellular cleavage to these bioactive components. Preclinical data demonstrate disease‐modifying activity in DMD animal models. Three placebo‐controlled studies in adult subjects assessed the safety, pharmacokinetics, and pharmacodynamics of single or multiple edasalonexent doses up to 6000 mg. Seventy‐nine adult subjects received edasalonexent, and 25 received placebo. Pharmacokinetic results were consistent with the intracellular cleavage of edasalonexent to its active components. Food increased plasma exposures of edasalonexent and salicyluric acid, an intracellularly formed metabolite of salicylic acid. The NF‐κB pathway and proteosome gene expression profiles in peripheral mononuclear cells were significantly decreased (P = .02 and P = .002, respectively) after 2 weeks of edasalonexent treatment. NF‐κB activity was inhibited following a single dose of edasalonexent but not by equimolar doses of salicylic acid and DHA. Edasalonexent was well tolerated, and the most common adverse events were mild diarrhea and headache. In first‐in‐human studies, edasalonexent was safe, well tolerated, and inhibited activated NF‐κB pathways, suggesting potential therapeutic utility in DMD regardless of the causative dystrophin mutation, as well as other NF‐κB–mediated diseases. |
format | Online Article Text |
id | pubmed-5412838 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-54128382017-05-15 A Novel NF‐κB Inhibitor, Edasalonexent (CAT‐1004), in Development as a Disease‐Modifying Treatment for Patients With Duchenne Muscular Dystrophy: Phase 1 Safety, Pharmacokinetics, and Pharmacodynamics in Adult Subjects Donovan, Joanne M. Zimmer, Michael Offman, Elliot Grant, Toni Jirousek, Michael J Clin Pharmacol Pharmacokinetics/Pharmacodynamics In Duchenne muscular dystrophy (DMD), NF‐κB is activated in skeletal muscle from infancy regardless of the underlying dystrophin mutation and drives inflammation and muscle degeneration while inhibiting muscle regeneration. Edasalonexent (CAT‐1004) is a bifunctional orally administered small molecule that covalently links 2 compounds known to inhibit NF‐κB, salicylic acid and docosahexaenoic acid (DHA). Edasalonexent is designed to inhibit activated NF‐κB upon intracellular cleavage to these bioactive components. Preclinical data demonstrate disease‐modifying activity in DMD animal models. Three placebo‐controlled studies in adult subjects assessed the safety, pharmacokinetics, and pharmacodynamics of single or multiple edasalonexent doses up to 6000 mg. Seventy‐nine adult subjects received edasalonexent, and 25 received placebo. Pharmacokinetic results were consistent with the intracellular cleavage of edasalonexent to its active components. Food increased plasma exposures of edasalonexent and salicyluric acid, an intracellularly formed metabolite of salicylic acid. The NF‐κB pathway and proteosome gene expression profiles in peripheral mononuclear cells were significantly decreased (P = .02 and P = .002, respectively) after 2 weeks of edasalonexent treatment. NF‐κB activity was inhibited following a single dose of edasalonexent but not by equimolar doses of salicylic acid and DHA. Edasalonexent was well tolerated, and the most common adverse events were mild diarrhea and headache. In first‐in‐human studies, edasalonexent was safe, well tolerated, and inhibited activated NF‐κB pathways, suggesting potential therapeutic utility in DMD regardless of the causative dystrophin mutation, as well as other NF‐κB–mediated diseases. John Wiley and Sons Inc. 2017-01-11 2017-05 /pmc/articles/PMC5412838/ /pubmed/28074489 http://dx.doi.org/10.1002/jcph.842 Text en © 2017, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs (http://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Pharmacokinetics/Pharmacodynamics Donovan, Joanne M. Zimmer, Michael Offman, Elliot Grant, Toni Jirousek, Michael A Novel NF‐κB Inhibitor, Edasalonexent (CAT‐1004), in Development as a Disease‐Modifying Treatment for Patients With Duchenne Muscular Dystrophy: Phase 1 Safety, Pharmacokinetics, and Pharmacodynamics in Adult Subjects |
title | A Novel NF‐κB Inhibitor, Edasalonexent (CAT‐1004), in Development as a Disease‐Modifying Treatment for Patients With Duchenne Muscular Dystrophy: Phase 1 Safety, Pharmacokinetics, and Pharmacodynamics in Adult Subjects |
title_full | A Novel NF‐κB Inhibitor, Edasalonexent (CAT‐1004), in Development as a Disease‐Modifying Treatment for Patients With Duchenne Muscular Dystrophy: Phase 1 Safety, Pharmacokinetics, and Pharmacodynamics in Adult Subjects |
title_fullStr | A Novel NF‐κB Inhibitor, Edasalonexent (CAT‐1004), in Development as a Disease‐Modifying Treatment for Patients With Duchenne Muscular Dystrophy: Phase 1 Safety, Pharmacokinetics, and Pharmacodynamics in Adult Subjects |
title_full_unstemmed | A Novel NF‐κB Inhibitor, Edasalonexent (CAT‐1004), in Development as a Disease‐Modifying Treatment for Patients With Duchenne Muscular Dystrophy: Phase 1 Safety, Pharmacokinetics, and Pharmacodynamics in Adult Subjects |
title_short | A Novel NF‐κB Inhibitor, Edasalonexent (CAT‐1004), in Development as a Disease‐Modifying Treatment for Patients With Duchenne Muscular Dystrophy: Phase 1 Safety, Pharmacokinetics, and Pharmacodynamics in Adult Subjects |
title_sort | novel nf‐κb inhibitor, edasalonexent (cat‐1004), in development as a disease‐modifying treatment for patients with duchenne muscular dystrophy: phase 1 safety, pharmacokinetics, and pharmacodynamics in adult subjects |
topic | Pharmacokinetics/Pharmacodynamics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5412838/ https://www.ncbi.nlm.nih.gov/pubmed/28074489 http://dx.doi.org/10.1002/jcph.842 |
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