REALM-DCM: A Phase 3, Multinational, Randomized, Placebo-Controlled Trial of ARRY-371797 in Patients With Symptomatic <i>LMNA</i> -Related Dilated Cardiomyopathy
Pablo García‐Pavía, José F. Rodríguez‐Palomares, Gianfranco Sinagra, Roberto Barriales‐Villa, Neal K. Lakdawala, Robert Gottlieb, Randal Goldberg, Perry Elliott, Patrice Lee, Hui‐Hua Li, Franca S. Angeli, Daniel P. Judge, Calum A. MacRae, Tomás Vicente Vera, Thomas V. McDonald, Juan C. Castillo, Stuart D. Katz, Stephen Pan, Juan R. Gimeno, Dinesh Gupta, Matthew R.G. Taylor, Cinzia Forleo, K. Afshar, Matthew T. Wheeler, Silvia G. Priori, Marc Vanderheyden, Iacopo Olivotto, José Tallaj, Johan Van Cleemput, Ana García Álvarez, April Stempien‐Otero, Víctor Alfonso Jiménez Díaz, Beatrice Musumeci, James S. Ware, Anjali Owens, Julia Cadrin‐Tourigny, W.H. Wilson Tang, Gregory A. Ewald, Vito Maurizio Parato, Alonzo E. Jones, Giuseppe Ambrosio, Cristian E. Botta, Kristina H. Haugaa, Kjell Andersen, Alejandro Hershson, Nabil M. Dib, Horacio A. Avaca, Serge Lepage, J. R. Martindale, Miguel E. Trevino, David Hinchman, Juan Loureyro, Frank McGrew, Saurabh Kapoor, Michael A. Burke, Joshua Williams, Armando García Castillo, F. Latif, John LeDoux, Yigal M. Pinto, Eloisa Arbustini, Caroline Coats, Pierpaolo Pellicori, Ray E. Hershberger, John Moses, Martin Gardner, Michael Hartleib, Mustafa Toma, Darryl N. Davis, Mark Hofmeyer, Farooq H. Sheikh, Marc Klapholz, Marco Metra, Eliud Samuel Montes Cruz, J R. Pineda
Abstract
BACKGROUND: LMNA ( lamin A/C )-related dilated cardiomyopathy is a rare genetic cause of heart failure. In a phase 2 trial and long-term extension, the selective p38α MAPK (mitogen-activated protein kinase) inhibitor, ARRY-371797 (PF-07265803), was associated with an improved 6-minute walk test at 12 weeks, which was preserved over 144 weeks. METHODS: REALM-DCM (NCT03439514) was a phase 3, randomized, double-blind, placebo-controlled trial in patients with symptomatic LMNA -related dilated cardiomyopathy. Patients with confirmed LMNA variants, New York Heart Association class II/III symptoms, left ventricular ejection fraction ≤50%, implanted cardioverter-defibrillator, and reduced 6-minute walk test distance were randomized to ARRY-371797 400 mg twice daily or placebo. The primary outcome was a change from baseline at week 24 in the 6-minute walk test distance using stratified Hodges-Lehmann estimation and the van Elteren test. Secondary outcomes using similar methodology included change from baseline at week 24 in the Kansas City Cardiomyopathy Questionnaire-physical limitation and total symptom scores, and NT-proBNP (N-terminal pro-B-type natriuretic peptide) concentration. Time to a composite outcome of worsening heart failure or all-cause mortality and overall survival were evaluated using Kaplan-Meier and Cox proportional hazards analyses. RESULTS: REALM-DCM was terminated after a planned interim analysis suggested futility. Between April 2018 and October 2022, 77 patients (aged 23–72 years) received ARRY-371797 (n=40) or placebo (n=37). No significant differences ( P >0.05) between groups were observed in the change from baseline at week 24 for all outcomes: 6-minute walk test distance (median difference, 4.9 m [95% CI, −24.2 to 34.1]; P =0.82); Kansas City Cardiomyopathy Questionnaire-physical limitation score (2.4 [95% CI, −6.4 to 11.2]; P =0.54); Kansas City Cardiomyopathy Questionnaire-total symptom score (5.3 [95% CI, −4.3 to 14.9]; P =0.48); and NT-proBNP concentration (−339.4 pg/mL [95% CI, −1131.6 to 452.7]; P =0.17). The composite outcome of worsening heart failure or all-cause mortality (hazard ratio, 0.43 [95% CI, 0.11–1.74]; P =0.23) and overall survival (hazard ratio, 1.19 [95% CI, 0.23–6.02]; P =0.84) were similar between groups. No new safety findings were observed. CONCLUSIONS: Findings from REALM-DCM demonstrated futility without safety concerns. An unmet treatment need remains among patients with LMNA -related dilated cardiomyopathy. REGISTRATION: URL: https://classic.clinicaltrials.gov ; Unique Identifiers: NCT03439514, NCT02057341, and NCT02351856.