Efficacy and Safety of ARRY-371797 in LMNA-Related Dilated Cardiomyopathy: A Phase 2 Study. (14th December 2022)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: Circulation. Volume 16:Number 1(2023)
• Page Start: e003730
• Publication Date: 2022-12-14
• Subjects: clinical trial -- lamin A/C -- LMNA-related dilated cardiomyopathy -- p38 MAPK; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Genetics -- Periodicals; Cardiovascular Diseases -- genetics; Precision Medicine; Periodical; Fulltext; Internet Resources; Periodicals; Electronic journals; Periodicals; 616.1042
• DOI: 10.1161/CIRCGEN.122.003730
• Languages: English
• ISSNs: 2574-8300

Abstract

Abstract : 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 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.