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Clinical Trial
. 2024 Dec;11(6):4201-4208.
doi: 10.1002/ehf2.14955. Epub 2024 Aug 15.

Characterization and natural history of patients with LMNA-related dilated cardiomyopathy in the phase 3 REALM-DCM trial

Pablo Garcia-Pavia  1   2   3   4   5 , Neal K Lakdawala  6   7 , Gianfranco Sinagra  8 , Tomas Ripoll-Vera  9   10   11   12 , Kia Afshar  13 , Silvia G Priori  5   14   15 , James S Ware  16   17 , Anjali Owens  18 , Huihua Li  19 , Franca S Angeli  19 , Perry Elliott  20 , Calum A MacRae  6   7 , Daniel P Judge  21
Affiliations
Clinical Trial

Characterization and natural history of patients with LMNA-related dilated cardiomyopathy in the phase 3 REALM-DCM trial

Pablo Garcia-Pavia et al. ESC Heart Fail. 2024 Dec.

Abstract

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.

Keywords: dilated cardiomyopathy; genetic diseases; heart failure; laminopathies; phase 3 clinical trial.

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Conflict of interest statement

PG‐P has served as a speaker in scientific meetings for Alexion, Alnylam, BridgeBio, Ionis/AstraZeneca, BMS, Novo Nordisk and Pfizer; has received funding from Alnylam and Pfizer for scientific meeting expenses; and has received consultancy fees from Alnylam, Attralus, BridgeBio, Neuroimmune, AstraZeneca, Novo Nordisk, Alexion, Intellia, LEXEO, BMS, Cytokinetics, Rocket and Pfizer. His institution has received research grants/educational support from Alnylam, AstraZeneca, BridgeBio, Intellia, Novo Nordisk and Pfizer. NKL has received consultancy fees from MyoKardia, Bristol Myers Squibb, Tenaya, Array BioPharma and Pfizer. GS reports consulting fees from Novartis, Impulse Dynamics, Novo Nordisk and Biotronik and speaker and honoraria from Novartis, Bayer, AstraZeneca, Boston Scientific, Vifor Pharma, Menarini and Akcea. TR‐V has been a speaker in scientific meetings for Alnylam, Pfizer, Amicus and Takeda; has received funding from Alnylam, Pfizer, Bayer and Chiesi for scientific meeting expenses; and has received consultancy fees from Alnylam, AstraZeneca, BMS, Amicus, Sanofi and Pfizer. His institution has received research grants/educational support from Pfizer, Boston and Abbott. SGP has received consultancy fees from Cardurion and Boston Scientific and research grant support from Solid Biosciences and Cardurion. JSW has received consultancy fees from MyoKardia, Foresite Labs, Pfizer and HealthLumen, and his institution has received research support from Bristol Myers Squibb and Pfizer. AO has received consulting or advisory board fees from Bristol Myers Squibb, Cytokinetics, Pfizer, BioMarin, Tenaya, Lexicon, Stealth and Renovacor and grant support from Bristol Myers Squibb. PE has received consultancy fees from Pfizer, BioMarin, Sarepta, Novo Nordisk and BMS. CAM has received consultancy fees from Affinia, Array BioPharma, AstraZeneca, Bayer, Bristol Myers Squibb, Design Therapeutics, Dewpoint, DiNAQOR, Merck, MyoKardia, Novartis and Pfizer and grant support from Bayer, Merck, Novartis and Sanofi. DPJ has received consultancy fees from ADRx, Alexion, Cytokinetics, LEXEO, Novo Nordisk, Pfizer and Tenaya Therapeutics. HL and FSA are employees of Pfizer and hold stock and/or stock options. KA has no relevant disclosures.

Figures

Figure 1
Figure 1
Patient disposition. NYHA, New York Heart Association.
See this image and copyright information in PMC

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