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REALM-DCM: A Phase 3, Multinational, Randomized, Placebo-Controlled Trial of ARRY-371797 in Patients With Symptomatic
Pablo Garcia-Pavia1, Jose Fernando Rodriguez Palomares2,3, Gianfranco Sinagra4
1Hospital Universitario Puerta de Hierro Majadahonda, CIBERCV, IDIPHISA, Universidad Francisco de Vitoria and Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (P.G.-P.).
Insights
The REALM-DCM trial found that ARRY-371797 did not improve outcomes for lamin A/C-related dilated cardiomyopathy. This selective p38α MAPK inhibitor showed no significant difference compared to placebo, indicating an unmet need for effective treatments.
Area of Science:
- Cardiology
- Genetics
- Pharmacology
Background:
- Dilated cardiomyopathy can be caused by genetic variants in the LMNA gene, affecting lamin A/C proteins.
- Selective p38α MAPK inhibitors, like ARRY-371797, have been investigated for potential therapeutic benefits in LMNA-related conditions.
- Previous studies suggested ARRY-371797 improved exercise capacity in LMNA-related dilated cardiomyopathy patients.
Purpose of the Study:
- To evaluate the efficacy and safety of ARRY-371797 in patients with symptomatic LMNA-related dilated cardiomyopathy.
- To assess the impact of ARRY-371797 on exercise capacity, cardiac function, and clinical outcomes.
Main Methods:
- The REALM-DCM trial was a phase 3, randomized, double-blind, placebo-controlled study.
- Patients received either ARRY-371797 (400 mg twice daily) or placebo, with primary endpoint being change in 6-minute walk test distance at 24 weeks.
- Secondary outcomes included changes in quality of life scores and NT-proBNP levels, as well as time to heart failure events or mortality.
Main Results:
- The trial was terminated early due to futility after an interim analysis.
- No statistically significant differences were observed between ARRY-371797 and placebo groups for the 6-minute walk test, quality of life scores, or NT-proBNP levels at 24 weeks.
- Composite endpoints for worsening heart failure or all-cause mortality, and overall survival, also showed no significant differences between the treatment arms.
Conclusions:
- ARRY-371797 demonstrated futility in treating LMNA-related dilated cardiomyopathy, with no significant efficacy observed compared to placebo.
- The study identified no new safety concerns associated with ARRY-371797.
- There remains a significant unmet medical need for effective therapies for patients suffering from LMNA-related dilated cardiomyopathy.
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.
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