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Efficacy and Safety of ARRY-371797 in LMNA-Related Dilated Cardiomyopathy: A Phase 2 Study

Lamin A/C gene (LMNA)-related dilated cardiomyopathy is a serious and life-threatening condition with a high unmet medical need. This phase 2 study assessed the effects of the oral selective p38 mitogen-activated protein kinase inhibitor ARRY-371797 on functional capacity and cardiac function in pat...

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Autores principales: MacRae, Calum A., Taylor, Matthew R.G., Mestroni, Luisa, Moses, John, Ashley, Euan A., Wheeler, Matthew T., Lakdawala, Neal K., Hershberger, Ray E., Sandor, Victor, Saunders, Michael E., Oliver, Colleen, Lee, Patrice A., Judge, Daniel P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9946172/
https://www.ncbi.nlm.nih.gov/pubmed/36515663
http://dx.doi.org/10.1161/CIRCGEN.122.003730
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author MacRae, Calum A.
Taylor, Matthew R.G.
Mestroni, Luisa
Moses, John
Ashley, Euan A.
Wheeler, Matthew T.
Lakdawala, Neal K.
Hershberger, Ray E.
Sandor, Victor
Saunders, Michael E.
Oliver, Colleen
Lee, Patrice A.
Judge, Daniel P.
author_facet MacRae, Calum A.
Taylor, Matthew R.G.
Mestroni, Luisa
Moses, John
Ashley, Euan A.
Wheeler, Matthew T.
Lakdawala, Neal K.
Hershberger, Ray E.
Sandor, Victor
Saunders, Michael E.
Oliver, Colleen
Lee, Patrice A.
Judge, Daniel P.
author_sort MacRae, Calum A.
collection PubMed
description Lamin A/C gene (LMNA)-related dilated cardiomyopathy is a serious and life-threatening condition with a high unmet medical need. This phase 2 study assessed the effects of the oral selective p38 mitogen-activated protein kinase inhibitor ARRY-371797 on functional capacity and cardiac function in patients with LMNA-related dilated cardiomyopathy. METHODS: Patients with LMNA-related dilated cardiomyopathy in New York Heart Association class II–IIIA, on background heart failure treatment, received ARRY-371797 100 or 400 mg twice daily for 48 weeks. The primary end point was change from baseline in the 6-minute walk test distance at 12 weeks. Secondary end points included changes over time in 6-minute walk test distance, NT-proBNP (N-terminal pro-B-type natriuretic peptide) concentration, left ventricular ejection fraction, and quality-of-life scores on the Kansas City Cardiomyopathy Questionnaire. Data from the 2 dose groups were combined. RESULTS: Twelve patients were enrolled; median (minimum, maximum) 6-minute walk test distance at baseline was 314 (246, 412) m. At week 12, the mean (80% CI) increase from baseline in 6-minute walk test distance was 69 (39, 100) m (median, 47 m). Median NT-proBNP concentration declined from 1409 pg/mL at baseline to 848 pg/mL at week 12. Mean left ventricular ejection fraction was stable at week 12. There was a trend toward improvement in Kansas City Cardiomyopathy Questionnaire Overall and Clinical Summary scores at week 12. No clinically significant drug-related safety concerns were identified. CONCLUSIONS: ARRY-371797 was well tolerated and resulted in potential increases in functional capacity and lower concentrations of cardiac biomarker NT-proBNP in patients with LMNA-related dilated cardiomyopathy. REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT02057341.
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spelling pubmed-99461722023-02-23 Efficacy and Safety of ARRY-371797 in LMNA-Related Dilated Cardiomyopathy: A Phase 2 Study MacRae, Calum A. Taylor, Matthew R.G. Mestroni, Luisa Moses, John Ashley, Euan A. Wheeler, Matthew T. Lakdawala, Neal K. Hershberger, Ray E. Sandor, Victor Saunders, Michael E. Oliver, Colleen Lee, Patrice A. Judge, Daniel P. Circ Genom Precis Med Original Articles Lamin A/C gene (LMNA)-related dilated cardiomyopathy is a serious and life-threatening condition with a high unmet medical need. This phase 2 study assessed the effects of the oral selective p38 mitogen-activated protein kinase inhibitor ARRY-371797 on functional capacity and cardiac function in patients with LMNA-related dilated cardiomyopathy. METHODS: Patients with LMNA-related dilated cardiomyopathy in New York Heart Association class II–IIIA, on background heart failure treatment, received ARRY-371797 100 or 400 mg twice daily for 48 weeks. The primary end point was change from baseline in the 6-minute walk test distance at 12 weeks. Secondary end points included changes over time in 6-minute walk test distance, NT-proBNP (N-terminal pro-B-type natriuretic peptide) concentration, left ventricular ejection fraction, and quality-of-life scores on the Kansas City Cardiomyopathy Questionnaire. Data from the 2 dose groups were combined. RESULTS: Twelve patients were enrolled; median (minimum, maximum) 6-minute walk test distance at baseline was 314 (246, 412) m. At week 12, the mean (80% CI) increase from baseline in 6-minute walk test distance was 69 (39, 100) m (median, 47 m). Median NT-proBNP concentration declined from 1409 pg/mL at baseline to 848 pg/mL at week 12. Mean left ventricular ejection fraction was stable at week 12. There was a trend toward improvement in Kansas City Cardiomyopathy Questionnaire Overall and Clinical Summary scores at week 12. No clinically significant drug-related safety concerns were identified. CONCLUSIONS: ARRY-371797 was well tolerated and resulted in potential increases in functional capacity and lower concentrations of cardiac biomarker NT-proBNP in patients with LMNA-related dilated cardiomyopathy. REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT02057341. Lippincott Williams & Wilkins 2022-12-14 /pmc/articles/PMC9946172/ /pubmed/36515663 http://dx.doi.org/10.1161/CIRCGEN.122.003730 Text en © 2022 The Authors. https://creativecommons.org/licenses/by-nc-nd/4.0/Circulation: Genomic and Precision Medicine is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.
spellingShingle Original Articles
MacRae, Calum A.
Taylor, Matthew R.G.
Mestroni, Luisa
Moses, John
Ashley, Euan A.
Wheeler, Matthew T.
Lakdawala, Neal K.
Hershberger, Ray E.
Sandor, Victor
Saunders, Michael E.
Oliver, Colleen
Lee, Patrice A.
Judge, Daniel P.
Efficacy and Safety of ARRY-371797 in LMNA-Related Dilated Cardiomyopathy: A Phase 2 Study
title Efficacy and Safety of ARRY-371797 in LMNA-Related Dilated Cardiomyopathy: A Phase 2 Study
title_full Efficacy and Safety of ARRY-371797 in LMNA-Related Dilated Cardiomyopathy: A Phase 2 Study
title_fullStr Efficacy and Safety of ARRY-371797 in LMNA-Related Dilated Cardiomyopathy: A Phase 2 Study
title_full_unstemmed Efficacy and Safety of ARRY-371797 in LMNA-Related Dilated Cardiomyopathy: A Phase 2 Study
title_short Efficacy and Safety of ARRY-371797 in LMNA-Related Dilated Cardiomyopathy: A Phase 2 Study
title_sort efficacy and safety of arry-371797 in lmna-related dilated cardiomyopathy: a phase 2 study
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9946172/
https://www.ncbi.nlm.nih.gov/pubmed/36515663
http://dx.doi.org/10.1161/CIRCGEN.122.003730
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