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. 2025 Aug 25:S0735-1097(25)07460-1.
doi: 10.1016/j.jacc.2025.08.019. Online ahead of print.

Echocardiographic Changes With Mavacamten in Nonobstructive Hypertrophic Cardiomyopathy: Exploratory Insights From the ODYSSEY-HCM Trial

Milind Y Desai  1 , Yuichiro Okushi  2 , Shada Jadam  2 , Iacopo Olivotto  3 , Anjali Owens  4 , Steven E Nissen  5 , Zoran B Popovic  2 , Pablo Garcia-Pavia  6 , Renato D Lopes  7 , Perry M Elliott  8 , Fabio Fernandes  9 , Jeffrey B Geske  10 , Lars Maier  11 , Kathy Wolski  5 , Qiuqing Wang  5 , Wael Jaber  5 , Zhiqun Gong  12 , Victoria Florea  12 , Matthew Fronheiser  12 , Arlene Leva  12 , Ron Aronson  12 , Theodore Abraham  13 ; ODYSSEY-HCM Investigators
Collaborators, Affiliations

Echocardiographic Changes With Mavacamten in Nonobstructive Hypertrophic Cardiomyopathy: Exploratory Insights From the ODYSSEY-HCM Trial

Milind Y Desai et al. J Am Coll Cardiol. .

Abstract

Background: Symptomatic nonobstructive hypertrophic cardiomyopathy (nHCM) lacks approved therapies. The ODYSSEY-HCM trial (A Study of Mavacamten in Non-Obstructive Hypertrophic Cardiomyopathy; NCT05582395), the largest to date in HCM patients, evaluating the efficacy of mavacamten in symptomatic adults with nHCM, did not demonstrate improvements in its primary endpoints (functional capacity and patient-reported health status).

Objectives: This exploratory analysis of the phase 3, randomized, placebo-controlled trial evaluated echocardiographic changes in nHCM patients from baseline to week 48.

Methods: Symptomatic nHCM patients were randomized to placebo or mavacamten (5 mg/d, titrated between 1 and 15 mg based on left ventricular ejection fraction [LVEF]). Echocardiographic assessments of LV systolic/diastolic function and left atrial (LA) function were performed at baseline and week 48.

Results: Among 580 randomized patients (mean age 56 ± 15 years, 45.9% women), baseline measures included LVEF (65.8 ± 4%), maximal LV wall thickness (20.8 ± 4 mm), LV mass index (122.3 ± 31 g/m2), average E/e' (13.3 ± 6), and LV-global longitudinal strain (-13.2 ± 4%). LA parameters included volume index (43.5 ± 16 mL/m2), reservoir strain (19.1 ± 9%), and conduit strain (-11.6 ± 6%). At week 48, there was significant placebo-corrected treatment difference with patients on mavacamten demonstrating significant reduction in maximal LV wall thickness (-2.1 mm [95% CI: -2.5 to -1.7 mm]), LV mass index (-3.8 g/m2 [95% CI: -7.1 to -0.5 g/m2]), and E/e' (-1.3 [95% CI: -2.0 to -0.7]), with a -5.3% [95% CI: -5.9% to -4.1%]; P < 0.01) reduction in LVEF. A reduction in LVEF <50% occurred in 62 patients (21.5%) in the mavacamten arm vs 5 (1.7%) in the placebo arm and recovered following drug interruption. Patients in the mavacamten group maintaining LVEF ≥50% throughout the study (n = 212) demonstrated an improvement in LV-global longitudinal strain at week 48 (-0.4% [95% CI: -0.8% to -0.05%]; P < 0.05). LA functional parameters including contractile (-1.1% [95% CI: -1.8% to -0.4%]) and conduit (-1.4% [95% CI: -0.6% to -2.3%]) strain also improved significantly at week 48 (P < 0.05), whereas LA volume was significantly reduced in patients without atrial fibrillation (-2.6 mL/m2 [95% CI: -4.7 to -1.11 mL/m2]; P = 0.009).

Conclusions: Symptomatic nHCM patients treated with mavacamten demonstrated directional improvements in markers of LV diastolic and LA function, modest regression in LV hypertrophy-related parameters, but 1 in 5 demonstrated an LVEF <50%, which reversed following therapy interruption.

Keywords: echocardiography; mavacamten; nonobstructive HCM; randomized placebo-controlled trial.

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Conflict of interest statement

Funding Support and Author Disclosures The ODYSSEY-HCM study was funded by Bristol Myers Squibb, Princeton, New Jersey. Dr Desai has received research and consulting agreements with Bristol Myers Squibb, Edgewise, Cytokinetics, Viz-AI, and Tenaya Therapeutics; and is on the scientific advisory board for Caristo Diagnostics. Dr Olivotto has received personal fees from Bristol Myers Squibb, Amicus, and Sanofi Genzyme; has received consultant/advisor fees from Bristol Myers Squibb, Cytokinetics, Sanofi Genzyme, Amicus, Bayer, Tenaya, Rocket Pharma, Edgewise and Lexeo; and has received research grants from Bristol Myers Squibb, Cytokinetics, Sanofi Genzyme, Amicus, Bayer, Menarini International, Chiesi and Boston Scientific. Dr Owens has been a consultant for Bristol Myers Squibb, Cytokinetics, Pfizer, Biomarin, Tenaya, Lexicon, Stealth, Edgewise, and Renovacor; and has received grant support for research from BMS. Dr Nissen’s institution, the Cleveland Clinic Center for Clinical Research (C5Research), has received funding from Abbvie, AstraZeneca, Amgen, Arrowhead, Bristol Myers Squibb, Kardigan, CRISPR Therapeutics, Eli Lilly, Esperion, Medtronic, MyoKardia, New Amsterdam Pharmaceuticals, Novartis, Pfizer, and Silence Therapeutics to perform clinical trials, and Dr Nissen is involved in conducting these clinical trials and consults for these pharmaceutical companies, but does not accept compensation. Dr Garcia-Pavia has received speaker fees from Alnylam Pharmaceuticals, AstraZeneca, Bayer, BMS, Bridgebio, Intellia, Ionis Pharmaceuticals, Novo Nordisk, Roche, and Pfizer; has received consulting fees from Alexion, Alnylam Pharmaceuticals, AskBio, AstraZeneca, ATTRalus, Bayer, Biomarin, BMS, Bridgebio, Cytokinetics, Edgewise, General Electric, Intellia, Idoven, Ionis Pharmaceuticals, Kardigan, Lexeo, Life Molecular Imaging, Pfizer, Neuroimmune, Novo Nordisk, and Rocket Pharmaceuticals; and has received institutional research/educational support from Alnylam Pharmaceuticals, AstraZeneca, Bayer, Bridgebio, Intellia, NovoNordisk, and Pfizer. Dr Lopes has received research grants or contracts from Amgen, Bristol Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi; has received funding for educational activities or lectures from Pfizer, Daiichi-Sankyo, and Novo Nordisk; and has received funding for consulting from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, and Novo Nordisk. Dr Fernandes has received consulting fees from Alnylam, AstraZeneca, Bristol Myers Squibb, and Pfizer. Dr Geske is a principal investigator for trials conducted by Bristol Myers Squibb, Cytokinetics and Lexicon. Dr Maier has received research and consulting agreements with Bristol Myers Squibb, AstraZeneca, Bayer, Boehringer, Pfizer, Pharmacosmos, and Zoll; and has received institutional grants from the Deutsche Forschungsgemeinschaft (DFG) grant SFB TR374, DFG grant MA 1982/11-1, and an EU grant (Horizon 2020) STRATIFY-HF ID 101080905. Ms Wolski and Q Wang are employees of C5 research. Dr Jaber is a consultant for Boston Scientific and Pfizer. Mr Gong, Dr Florea, Dr Fronheiser, Dr Leva, and Dr Aronson are employees of and own stock in Bristol Myers Squibb. Dr Abraham has received research grants/clinical trial support from BMS, Cytokinetics, Tenaya, and Edgewise. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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