Advances in Treatment for Non-Obstructive Hypertrophic Cardiomyopathy (nHCM)

Unmet Need for Targeted Therapies in nHCM

Non-obstructive hypertrophic cardiomyopathy (nHCM) is a genetic heart condition characterized by the thickening of the heart muscle without obstruction of blood flow. This thickening leads to impaired diastolic function, meaning the heart struggles to relax and fill properly during the diastolic phase of the cardiac cycle. Unlike obstructive HCM (oHCM), where the obstruction of blood flow is a significant issue and targeted therapies like Mavacamten have been approved, nHCM currently lacks any approved targeted treatments. This gap highlights an urgent need for effective therapies tailored specifically to nHCM.

Prevalence & Symptoms

Hypertrophic cardiomyopathy (HCM) affects approximately 1 in 200 to 1 in 500 individuals in the general population. Among these, about 30% of cases are non-obstructive. Patients with nHCM often experience debilitating symptoms such as shortness of breath, chest pain, fatigue, and exercise intolerance. These symptoms primarily result from diastolic dysfunction and impaired ventricular relaxation, which can severely impact the quality of life.

Prognosis for nHCM Patients

The prognosis for nHCM can vary widely. While some patients live symptom-free with normal life expectancy, others face progressive heart failure, arrhythmias, and a higher risk of sudden cardiac death. Studies have shown that nHCM patients have a significant risk of morbidity, with a 1.6% annual mortality rate and higher incidences of sustained ventricular tachycardia or fibrillation compared to oHCM. Detailed sudden cardiac death risk stratification and continuous monitoring are crucial for managing nHCM effectively.

Recent Clinical Trial Results

Recent advancements in clinical research have brought hope for better management of nHCM. Here are some notable studies and their findings:

1. Mavacamten (MAVERICK-HCM, Phase II):

• Overview: Mavacamten is a myosin inhibitor developed by Bristol Myers Squibb initially approved for treating obstructive HCM (oHCM). The MAVERICK-HCM trial explored its efficacy in nHCM patients.

• Results: The trial showed some clinical benefits, but Mavacamten's impact on nHCM was less conclusive compared to its efficacy in oHCM. Notably, improvements in biomarkers like NT-proBNP and cardiac troponin I were observed, suggesting potential benefits.
  

1. Aficamten (REDWOOD-HCM, Phase II):

• Overview: Aficamten, developed by Cytokinetics, is another myosin inhibitor demonstrating promising results. The REDWOOD-HCM trial focused on its effects in nHCM patients.

• Results: Aficamten showed slightly superior data compared to Mavacamten, with significant improvements in diastolic function and reduced wall stress. It also showed a favorable impact on heart failure symptoms and cardiac biomarkers, positioning it as a potential candidate for nHCM treatment.
  

1. Ninerafaxstat (IMPROVE-HCM, Phase II):

• Overview: Ninerafaxstat (Imbria) is a novel cardiac mitotrope that enhances glucose metabolism by partially inhibiting fatty acid oxidation.

• Results: The trial revealed improvement in the health status of a cohort of severely symptomatic nHCM patients. While improvements in NT-proBNP and other biomarkers were less pronounced compared to the myosin inhibitors, the drug demonstrated a favorable safety profile and potential benefits in exercise capacity and diastolic function.

Targeting Cardiac Fibrosis: A Promising Approach

One of the most promising approaches to treating nHCM is targeting cardiac fibrosis, a major contributor to diastolic dysfunction and heart failure in nHCM. HAYA Therapeutics is at the forefront of this approach, developing an antisense oligonucleotide targeting Wisper, a cardiac fibroblast-enriched long non-coding RNA (lncRNA) involved in fibrosis. This strategy leverages the specificity of lncRNAs, potentially reducing the risk of off-target effects that are common with other anti-fibrotic therapies.

Future Directions & Ongoing Research

Ongoing research continues to explore and develop new therapeutic options for nHCM. Large Phase III trials for drugs like Aficamten (ACACIA-HCM) and Mavacamten (ODYSSEY-HCM) are underway, aiming to provide more robust data on their efficacy and safety in nHCM. Additionally, preclinical studies on targeting Wisper lncRNA offer promising insights into reducing cardiac fibrosis and improving heart function.

As we advance our understanding of nHCM and develop more targeted therapies, the outlook for patients with this challenging condition is becoming increasingly hopeful. By addressing the specific needs of nHCM patients, these innovative treatments have the potential to significantly enhance their quality of life and overall prognosis.

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