Efficacy and Safety of ARRY-371797 in LMNA-Related Dilated Cardiomyopathy: A Phase 2 Study. Circulation. Genomic and precision medicine MacRae, C. A., Taylor, M. R., Mestroni, L., Moses, J., Ashley, E. A., Wheeler, M. T., Lakdawala, N. K., Hershberger, R. E., Sandor, V., Saunders, M. E., Oliver, C., Lee, P. A., Judge, D. P. 2022: e003730


BACKGROUND: 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 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.

View details for DOI 10.1161/CIRCGEN.122.003730

View details for PubMedID 36515663