Patients with nonobstructive hypertrophic cardiomyopathy (nHCM) often present with symptoms and physiology resembling heart failure with preserved ejection fraction: exertional dyspnea, limited exercise capacity, chronotropic incompetence, microvascular ischemia, diastolic dysfunction, and a small, stiff left ventricular (LV) cavity. Current guidelines recommend beta-blockers (BBs) or nondihydropyridine calcium channel blockers (NDHP-CCBs) for symptomatic relief, with no disease-modifying medical therapy available.¹

Given the remarkable efficacy of cardiac myosin inhibitors in obstructive hypertrophic cardiomyopathy (oHCM), the natural question became whether sarcomere modulation could also improve symptoms in nHCM. The MAVERICK-HCM (Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy) phase 2 study provided an early biologic signal. Mavacamten produced large reductions in N-terminal pro–B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I (hs-cTnI) levels compared with placebo, and these biomarker shifts aligned with improvements in diastolic parameters.² These findings suggested that myosin inhibition may reduce wall stress and favorably influence myocardial relaxation in nHCM.

The MAVERICK-HCM study findings set the stage for the ODYSSEY-HCM (A Study of Mavacamten in Nonobstructive Hypertrophic Cardiomyopathy), the first phase 3 study evaluating whether such biologic changes translate into improved symptoms or exercise capacity. In the ODYSSEY-HCM, 580 adults with symptomatic nHCM were randomly assigned to mavacamten or placebo for 48 weeks. Inclusion criteria were rigorous: Patients had to be symptomatic (New York Heart Association [NYHA] class II or III symptoms), have preserved (≥60%) left ventricular ejection fraction (LVEF), and demonstrate functional limitation (Kansas City Cardiomyopathy Questionnaire Clinical Summary Score [KCCQ-CSS] ≤85). Crucially, to define the nonobstructive phenotype, patients were required to have left ventricular outflow tract (LVOT) gradient <30 mm Hg at rest and <50 mm Hg with provocation. This criterion allowed for the inclusion of patients with mild or latent obstruction below these thresholds but excluded classic oHCM physiology. The dual primary endpoints were the changes in peak oxygen consumption (VO₂) and KCCQ-CSS.³

Clinically, the trial findings were neutral. Neither peak VO₂ (difference 0.47 mL/kg/min; p = 0.07) nor KCCQ-CSS (difference 2.7 points; p = 0.06) improved significantly with mavacamten compared with placebo. Although peak VO₂ and KCCQ-CSS improved in the treatment arm, they also improved in the placebo arm, diluting the treatment effect.³

However, the biologic response in the ODYSSEY-HCM was striking. In an exploratory analysis, mavacamten produced a 58% reduction in NT-proBNP levels and a 51% reduction in hs-cTnI levels, with no corresponding changes in the placebo arm. These curves diverged as early as 4 weeks and remained separated through week 48.^3,4 Echocardiographic parameters showed complementary improvement, including reductions in wall thickness, left atrial size, and the ratio of mitral inflow velocity to mitral annular velocity (Figure 1).⁴

Figure 1: Biology Improves, Symptoms Do Not: The Central Finding of the ODYSSEY-HCM

Mavacamten reduces myosin-actin cross-bridge cycling, leading to reverse remodeling reflected by reductions in NT-proBNP levels (-58%), hs-cTnI levels (-51%), WT, LAVi, and E/e′. Despite these biologic improvements, clinical outcomes in the ODYSSEY-HCM were neutral, with no significant changes in peak VO₂, KCCQ-CSS, or NYHA class at 48 weeks. Created in BioRender. Adel, F. (2026) https://BioRender.com/c7zwnzj
ATP = adenosine triphosphate; E/e′ = ratio of early mitral inflow to annular tissue velocity; hs-cTnI = high-sensitivity cardiac troponin I; KCCQ-CSS = Kansas City Cardiomyopathy Questionnaire Clinical Summary Score; LAVi = left atrial volume index; NT-proBNP = N-terminal pro–B-type natriuretic peptide; NYHA = New York Heart Association; ODYSSEY-HCM = A Study of Mavacamten in Nonobstructive Hypertrophic Cardiomyopathy; WT = wall thickness; VO₂ = oxygen consumption.

Taken together, these findings make it clear that mavacamten induced reverse remodeling in nHCM. What did not change was how patients felt or how they performed on objective exercise testing—the myocardium responded, the patient did not.

Several factors likely explain this disconnect. Symptoms in nHCM arise from a complex interplay of diastolic dysfunction, impaired LV reserve, microvascular ischemia, chronotropic incompetence, pulmonary hypertension, and abnormal energetics. Hypercontractility is only one contributor. Reducing myosin-actin cross-bridge cycling may not be sufficient to meaningfully alter peak VO₂ in the short term.³ Additionally, many patients in the ODYSSEY-HCM had long-standing (mean ~10 years) disease with fixed structural remodeling and comorbidities.³ Reverse remodeling may take years, not months, to influence exercise capacity in this population. Additionally, given the mean preceding disease duration, some patients may have had burned-out oHCM, although they no longer had LVOT obstruction due to progressive fibrosis.

Another barrier is the safety ceiling. A substantial portion of patients receiving mavacamten (21.5% vs. 1.7% in placebo) developed a decline in LVEF to <50%.³ This decline necessitated dose interruptions, which likely prevented the sustained sarcomere modulation required to improve diastolic filling.

The biologic effects observed in nHCM are not unique to mavacamten. In the REDWOOD-HCM (Randomized Evaluation of Dosing With CK-3773274 in Obstructive Outflow Disease in HCM) open-label analysis, aficamten produced clinically meaningful improvements, with 55% of patients demonstrating improvement by at least one NYHA class, a median NT-proBNP level reduction of 56% (from 1105 to 593 pg/mL), and improvements in KCCQ-CSS by +11 ± 15 points, alongside favorable safety and preserved systolic function.⁵ These findings provided the rationale for the ACACIA-HCM (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic nHCM), the ongoing phase 3 randomized trial evaluating aficamten in symptomatic nHCM.⁶

In contrast, the performance of myosin inhibitors in obstructive HCM has been consistently robust. In the EXPLORER-HCM (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy), mavacamten produced a clear clinical signal: 37% of patients met the primary endpoint versus 17% with placebo, accompanied by a +1.4 mL/kg/min increase in peak VO₂ (vs. 0.0) and improvement by at least one NYHA class in 65% compared with 31% of patients. Resting and postexercise LVOT gradients fell dramatically (resting by -36 mm Hg and postexercise by -47 mm Hg), translating into meaningful improvements in patient-reported health status.⁷

The SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM) trial reproduced this success with aficamten, achieving its primary endpoint in 62% versus 18% of patients, improving peak VO₂ by +1.8 mL/kg/min (vs. +0.6 mL/kg/min), and reducing postexercise LVOT gradients by -55 mm Hg versus -10 mm Hg. Health status metrics improved accordingly, with 12- to 14-point gains in KCCQ-CSS versus 4- to 5-point gains with placebo.⁸ The VALOR-HCM (Mavacamten in Adults With Symptomatic Obstructive HCM Who Are Eligible for Septal Reduction Therapy) trial results extended these findings to a real-world decision point: whether patients still needed septal reduction therapy (SRT). By week 16, only 18% of mavacamten-treated patients continued to meet the criteria for SRT compared with 77% in the placebo group, with improvement by at least one NYHA class in 63% versus 21% and substantial reduction in resting gradients (-37 mm Hg vs. -8 mm Hg).⁹ Collectively, these trial findings underscore a central principle: nHCM is not simply oHCM without a gradient, and its symptom drivers and therapeutic responsiveness are fundamentally different (Table 1).

Table 1: Differential Response to Myosin Inhibition in nHCM vs. oHCM

afic = aficamten; E/e′ = ratio of early mitral inflow to annular tissue velocity; EXPLORER-HCM = Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy; hs-cTnI = high-sensitivity cardiac troponin I; KCCQ-CSS = Kansas City Cardiomyopathy Questionnaire Clinical Summary Score; LAVi = left atrial volume index; LVEF = left ventricular ejection fraction; LVOT = left ventricular outflow tract; mava = mavacamten; NA = not applicable; nHCM = nonobstructive hypertrophic cardiomyopathy; NYHA = New York Heart Association; NT-proBNP = N-terminal pro–B-type natriuretic peptide; oHCM = obstructive hypertrophic cardiomyopathy; REDWOOD-HCM = Randomized Evaluation of Dosing With CK-3773274 in Obstructive Outflow Disease in HCM; SRT = septal reduction therapy; VALOR-HCM = Mavacamten in Adults With Symptomatic Obstructive HCM Who Are Eligible for Septal Reduction Therapy; WT = wall thickness; VO₂ = oxygen consumption.

At present, myosin inhibitors should not be used to treat symptomatic nHCM outside of randomized controlled trials (RCTs). Despite a lack of robust RCT data, guideline-directed management remains focused on BBs and NDHP-CCBs, aggressive management of atrial fibrillation, treatment of comorbidities, and cautious use of diuretics.¹

The ODYSSEY-HCM results should not be viewed as the end of sarcomere modulation in nHCM. Rather, they clarify the biology: The myocardium responds, but the patient does not, at least not within current timelines, dosing strategies, or clinical endpoints. This tension highlights the need for better phenotyping, earlier therapeutic intervention, longer-duration trials, and possibly combination approaches targeting microvascular dysfunction, energetics, or fibrosis alongside sarcomere inhibition in nHCM.

References

1. Writing Committee Members, Ommen SR, Ho CY, et al. 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR guideline for the management of hypertrophic cardiomyopathy: a report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2024;83(23):2324-2405. doi:10.1016/j.jacc.2024.02.014
2. Ho CY, Mealiffe ME, Bach RG, et al. Evaluation of mavacamten in symptomatic patients with nonobstructive hypertrophic cardiomyopathy. J Am Coll Cardiol. 2020;75(21):2649-2660. doi:10.1016/j.jacc.2020.03.064
3. Desai MY, Owens AT, Abraham T, et al. Mavacamten in symptomatic nonobstructive hypertrophic cardiomyopathy. N Engl J Med. 2025;393(10):961-972. doi:10.1056/NEJMoa2505927
4. Desai MY, Olivotto I, Abraham T, et al. Effects of Mavacamten on cardiac biomarkers in nonobstructive hypertrophic cardiomyopathy: insights from the ODYSSEY-HCM trial. J Am Coll Cardiol. 2025;86(24):2418-2433. doi:10.1016/j.jacc.2025.08.017
5. Masri A, Sherrid MV, Abraham TP, et al. Efficacy and safety of aficamten in symptomatic nonobstructive hypertrophic cardiomyopathy: results from the REDWOOD-HCM trial, cohort 4. J Card Fail. 2024;30(11):1439-1448. doi:10.1016/j.cardfail.2024.02.020
6. Cytokinetics. Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic nHCM (ACACIA-HCM) (ClinicalTrials.gov website). 2025. Available at: https://clinicaltrials.gov/study/NCT06081894. Accessed 01/12/2026.
7. Olivotto I, Oreziak A, Barriales-Villa R, et al. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2020;396(10253):759-769. doi:10.1016/S0140-6736(20)31792-X
8. Maron MS, Masri A, Nassif ME, et al. Aficamten for symptomatic obstructive hypertrophic cardiomyopathy. N Engl J Med. 2024;390(20):1849-1861. doi:10.1056/NEJMoa2401424
9. Desai MY, Owens A, Wolski K, et al. Mavacamten in patients with hypertrophic cardiomyopathy referred for septal reduction: week 56 results from the VALOR-HCM randomized clinical trial. JAMA Cardiol. 2023;8(10):968-977. doi:10.1001/jamacardio.2023.3342