REALM-DCM: A Phase 3, Multinational, Randomized, Placebo-Controlled Trial of ARRY-371797 in Patients With Symptomatic
LMNA
-Related Dilated Cardiomyopathy
Authors: Garcia-Pavia Pablo , Palomares Jose Fernando Rodriguez , Sinagra Gianfranco , Barriales-Villa Roberto , Lakdawala Neal K. , Gottlieb Robert L. , Goldberg Randal I. , Elliott Perry , Lee Patrice , Li Huihua , Angeli Franca S. , Judge Daniel P. , MacRae Calum A. , Ripoll Vera Tomas V. , McDonald Thomas V. , Carlos Castillo Dominguez Juan , Katz Stuart D. , Pan Stephen , Gimeno Blanes Juan R. , Gupta Dinesh K. , Taylor Matthew R.G. , Forleo Cinzia , Afshar Kia , Wheeler Matthew T. , Priori Silvia G. , Vanderheyden Marc , Olivotto Iacopo , Tallaj Jose A. , Van Cleemput Johan , Garcia Alvarez Ana , Stempien-Otero April C. , Alfonso Jimenez Diaz Victor , Beatrice Musumeci Maria , Ware James , Owens Anjali T. , Cadrin-Tourigny Julia , Tang W. H. Wilson , Ewald Gregory A. , Maurizio Parato Vito , Jones Alonzo E. , Ambrosio Giuseppe , Botta Cristian E. , Haugaa Kristina H. , Andersen Kjell , Hershson Alejandro R. , Dib Nabil M. , Avaca Horacio A. , Lepage Serge , Martindale Jeffrey , Trevino Miguel E. , Hinchman David A. , Loureyro Juan , McGrew Frank A. , Kapoor Saurabh , Burke Michael A. , Williams Joshua , Castillo Armando Garcia , Latif Farhana , LeDoux John , Pinto Yigal , Arbustini Eloisa , Coats Caroline , Pellicori Pierpaolo , Hershberger Ray , Moses John , Gardner Martin , Hartleib Michael C. , Toma Mustafa , Davis Darryl , Hofmeyer Mark , Sheikh Farooq , Klapholz Marc , Metra Marco , Samuel Montes Cruz Eliud , Pineda J R. 
Published: July 2024

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.