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Characterization and natural history of patients with LMNA-related dilated cardiomyopathy in the phase 3 REALM-DCM
Pablo Garcia-Pavia1,2,3,4,5, Neal K Lakdawala6,7, Gianfranco Sinagra8
1Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain.
Insights
LMNA-related dilated cardiomyopathy (DCM) causes significant illness and death, even with standard care. Heart failure measures varied but linked to disease severity, highlighting an unmet treatment need.
Area of Science:
- Cardiology
- Genetics
- Heart Failure Research
Background:
- LMNA-related dilated cardiomyopathy (DCM) is a rare genetic heart condition with an unclear clinical picture.
- The REALM-DCM trial, investigating a therapy for LMNA-related DCM, was stopped early due to futility.
- This study analyzes pooled data from the REALM-DCM trial to describe the characteristics and progression of LMNA-related DCM.
Purpose of the Study:
- To descriptively characterize the phenotype and progression of LMNA-related DCM in a contemporary patient cohort.
- To evaluate common heart failure (HF) measures in patients with LMNA-related DCM.
- To identify the unmet treatment needs in LMNA-related DCM patients.
Main Methods:
- Utilized pooled data from the REALM-DCM trial, which enrolled 77 patients with LMNA-related DCM, NYHA Class II/III HF symptoms, and implanted defibrillators.
- Collected baseline data on demographics, genetic variants, and HF measures including left ventricular ejection fraction (LVEF), 6-minute walk test (6MWT) distance, Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) score, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration.
- Analyzed patient data over a median follow-up of 73 weeks, assessing changes in HF measures and clinical outcomes.
Main Results:
- The cohort (median age 53 years, 57% male) predominantly had confirmed pathogenic LMNA variants (88%) and NYHA Class II symptoms (79%).
- Baseline HF measures showed variability: median LVEF 42%, 6MWT 403m, KCCQ-OS 67, and NT-proBNP 866 pg/mL. Patients with NYHA Class III symptoms had numerically lower LVEF and 6MWT, and higher NT-proBNP compared to Class II.
- During follow-up, 13% experienced worsening HF or all-cause death, and 8% died from all causes, indicating significant morbidity and mortality despite standard care.
Conclusions:
- LMNA-related DCM is associated with substantial morbidity and mortality, even with current standard management.
- Standard HF measures like 6MWT, KCCQ-OS, and NT-proBNP demonstrated variability but correlated with NYHA functional class.
- There is a clear unmet need for effective therapies for patients suffering from LMNA-related DCM.
Aims:
LMNA-related dilated cardiomyopathy (DCM) is a rare disease with an incompletely defined phenotype. The phase 3 REALM-DCM trial evaluated a potential disease-modifying therapy for LMNA-related DCM but was terminated due to futility without safety concern. This study utilized pooled data from REALM-DCM to descriptively characterize the phenotype and progression of LMNA-related DCM in a contemporary cohort of patients using common heart failure (HF) measures.
Methods:
REALM-DCM enrolled patients with stable LMNA-related DCM, an implanted cardioverter defibrillator or cardiac resynchronization therapy defibrillator, and New York Heart Association (NYHA) Class II/III HF symptoms.
Results:
Between 2018 and 2022, 77 patients took part in REALM-DCM. The median patient age was 53 years (range: 23-72), and 57% were male. Overall, 88% of patients had a pathogenic or likely pathogenic LMNA variant, and 12% had a variant of uncertain significance with a concordant phenotype. Among patients with confirmed sequencing, 55% had a missense variant. Atrial fibrillation was present in 60% of patients; 79% of all patients had NYHA Class II and 21% had NYHA Class III HF symptoms at baseline. Median (range) left ventricular ejection fraction (LVEF), 6 min walk test (6MWT) distance, Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) score and N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration at baseline were 42% (23-62), 403 m (173-481), 67 (18-97) and 866 pg/mL (57-5248), respectively. LVEF, 6MWT distance and KCCQ-OS score were numerically lower in patients who had NYHA Class III versus II symptoms at baseline (LVEF: 38% vs. 43%; 6MWT distance: 326 vs. 413 m; and KCCQ-OS score: 43 vs. 70), whereas NT-proBNP concentration was higher (1216 vs. 799 pg/mL). Median follow-up was 73 weeks (range: 0.4-218; 73 in NYHA Class II and 75 in NYHA Class III). Patients displayed variable change from baseline in 6MWT, KCCQ-OS and NT-proBNP values during follow-up. Overall, 25% of patients experienced ventricular tachycardia, and 8% had ventricular fibrillation. Ten (13%) patients met the composite endpoint of worsening HF (adjudicated HF-related hospitalization or urgent care visit) or all-cause death; six had NYHA Class II and four had NYHA Class III at baseline. All-cause mortality occurred in 6 (8%) patients; three had NYHA Class II and three had NYHA Class III symptoms at baseline.
Conclusions:
Findings confirm the significant morbidity and mortality associated with LMNA-related DCM despite the standard of care management. Typical measures of HF, including 6MWT distance, KCCQ-OS score and NT-proBNP concentration, were variable but correlated with NYHA class. An unmet treatment need remains among patients with LMNA-related DCM. NCT03439514.
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