High-Impact Highlights
Significant Biomarker Reduction
Treatment with mavacamten led to a 58% reduction in NT-proBNP and a 51% reduction in high-sensitivity cardiac troponin I (hs-cTnI) compared to placebo over 48 weeks.
Rapid and Sustained Response
The decline in cardiac biomarkers occurred early in the treatment course and was maintained throughout the study period, indicating a consistent effect on myocardial physiology.
Clinical Correlates
Baseline NT-proBNP levels were strongly associated with female sex, higher NYHA functional class, and echocardiographic markers of diastolic dysfunction, whereas hs-cTnI was linked primarily to LV mass index.
The Clinical Challenge of Nonobstructive HCM
Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular (LV) hypertrophy. While obstructive HCM (oHCM) has seen significant therapeutic advances with the approval of cardiac myosin inhibitors, nonobstructive HCM (nHCM) remains a therapeutic void. Patients with nHCM suffer from debilitating symptoms including dyspnea, exercise intolerance, and chest pain, largely driven by impaired diastolic relaxation, increased wall stress, and microvascular ischemia rather than mechanical outflow obstruction. Currently, no therapies are specifically approved for symptomatic nHCM, leaving clinicians to rely on off-label use of beta-blockers or calcium channel blockers, which often provide suboptimal relief.
The ODYSSEY-HCM Trial: Redefining the Landscape
The ODYSSEY-HCM trial (NCT05582395) represents the largest randomized controlled trial to date in the nHCM population. It evaluated mavacamten, a first-in-class selective allosteric inhibitor of cardiac myosin, which reduces the number of myosin-actin cross-bridges. By doing so, mavacamten targets the underlying pathophysiology of HCM—hypercontractility and impaired relaxation. Although the primary results of ODYSSEY-HCM did not demonstrate significant improvements in functional capacity (peak VO2) or patient-reported health status, the exploratory analysis of cardiac biomarkers provides critical insights into the drug’s biological activity in this specific phenotype.
Study Design and Methodology
The study randomized 580 symptomatic adults with nHCM to receive either mavacamten or a placebo for 48 weeks. The mavacamten dose was initiated at 5 mg daily and titrated (ranging from 1 to 15 mg) based on left ventricular ejection fraction (LVEF) to ensure safety. The exploratory objectives focused on two primary cardiac biomarkers: N-terminal pro-B-type natriuretic peptide (NT-proBNP), a marker of hemodynamic wall stress, and high-sensitivity cardiac troponin I (hs-cTnI), a marker of ongoing myocardial injury. Measurements were taken at baseline and at regular intervals through week 48, alongside comprehensive echocardiographic and clinical assessments.
Key Findings: Biomarker Dynamics
The results of this exploratory analysis demonstrate a profound and statistically significant impact of mavacamten on the biochemical profile of nHCM patients.
NT-proBNP Reductions
At baseline, the median NT-proBNP was 917.5 ng/L, reflecting significant myocardial stress. By week 48, the mavacamten group exhibited a 58% reduction in NT-proBNP levels (geometric mean ratio: 0.42; 95% CI: 0.37-0.47; P < 0.001). In contrast, the placebo group showed no significant change. This reduction is particularly noteworthy because NT-proBNP is a well-established prognostic marker in HCM, correlated with the risk of heart failure and atrial fibrillation.
hs-cTnI Reductions
Myocardial injury, as measured by hs-cTnI, also saw a dramatic decline. From a baseline median of 29.1 ng/L, mavacamten treatment resulted in a 51% reduction by week 48 (geometric mean ratio: 0.49; 95% CI: 0.45-0.53; P < 0.001). This suggests that mavacamten may mitigate the chronic, low-grade myocardial ischemia and cardiomyocyte death that characterize the natural history of nHCM.
Baseline Determinants of Biomarkers
The researchers performed a multivariable analysis to understand what clinical factors drive biomarker elevation in nHCM. Higher baseline NT-proBNP was associated with female sex, higher body mass index (BMI), more severe NYHA functional class, increased maximal LV wall thickness, larger left atrial volume index, and higher E/e’ ratio (a surrogate for filling pressures). Conversely, hs-cTnI elevations were primarily associated with younger age and a higher LV mass index, suggesting that troponin release in nHCM may be more closely tied to the degree of hypertrophy and metabolic demand.
Expert Commentary: Reconciling the Data
The disconnect between the dramatic improvement in biomarkers and the neutral primary functional endpoints in ODYSSEY-HCM presents a complex clinical puzzle. One possibility is that 48 weeks is insufficient to observe the macroscopic reverse remodeling required to improve exercise capacity in nHCM, where fibrosis and diastolic dysfunction are deeply entrenched. The marked reduction in NT-proBNP and hs-cTnI indicates that mavacamten is effectively ‘unloading’ the heart at a molecular level. However, functional capacity is a multifactorial metric influenced by peripheral factors, deconditioning, and comorbidities, which may not respond as rapidly as biochemical markers. Mechanistically, the reduction in biomarkers suggests that mavacamten improves diastolic relaxation and reduces the energetic cost of contraction. This ‘biological success’ may eventually translate into clinical benefits if treatment is maintained over a longer period, potentially leading to adaptive structural remodeling.
Summary and Clinical Implications
The ODYSSEY-HCM biomarker analysis confirms that mavacamten exerts a potent biological effect in patients with nonobstructive HCM, significantly lowering markers of wall stress and cellular injury. While these changes did not result in improved functional capacity within the 48-week trial window, they provide a strong rationale for further investigation into the long-term effects of myosin inhibition. For clinicians, these findings underscore the utility of NT-proBNP and hs-cTnI as sensitive indicators of therapeutic response in HCM. The future of nHCM management may depend on whether these biochemical improvements are precursors to meaningful structural changes and improved long-term outcomes.
Funding and Trial Information
The ODYSSEY-HCM trial was supported by Bristol Myers Squibb. ClinicalTrials.gov Identifier: NCT05582395.
References
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 Dec 16;86(24):2418-2433. doi: 10.1016/j.jacc.2025.08.017. Epub 2025 Aug 27. PMID: 40864018.
