MAVACAMTEN: First and only cardiac myosin inhibitor
- ACS BCP
- May 25
- 3 min read
1. Introduction
Mavacamten, marketed under the brand name Camzyos, is a first-in-class cardiac myosin inhibitor developed by Bristol Myers Squibb. It is primarily used for the treatment of obstructive hypertrophic cardiomyopathy (oHCM), a genetic condition characterized by excessive thickening of the heart muscle, leading to impaired blood flow and increased cardiac workload. Unlike traditional therapies that focus on symptom management, Mavacamten directly targets the underlying hypercontractility of the heart muscle, offering a disease-modifying approach
2. About Hypertrophic cardiomyopathy (HCM)
Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiac disorder. This monogenetic disease is characterized by left ventricular hypertrophy in the absence of secondary causes, such as increased loading conditions (eg, hypertension or valvular pathology) or infiltrative disorders. HCM is an autosomal dominant disease associated with cardiac sarcomeres, myosin-binding protein C, and β-myosin heavy chain mutations.
Initially asymptomatic, HCM is characterized by a gradual progression of shortness of breath on exertion and worsening quality of life due to dynamic obstruction of the left ventricular outflow tract (LVOT). Obstructive HCM arises from myofibrillar disarray, leading to septal hypertrophy and an abnormal subvalvular mitral apparatus, which causes systolic anterior motion of one or both mitral leaflets. The prognosis for HCM is variable, with symptomatic heart failure and sudden cardiac death occurring in a small subset of patients.
3. Mechanism of Action
Mavacamten is an allosteric, selective, and reversible inhibitor of cardiac myosin ATPase. This first-in-class medication reduces the formation of actin-myosin cross-bridges, thus reducing the probability of systolic and diastolic cross-bridge formation. Excessive myosin-actin cross-bridge arrangement and dysregulation of the relaxed state are characteristic of HCM. Mavacamten promotes an energy-sparing and super-relaxed state that translates as a reduction in LVOT obstruction and improvement of cardiac filling pressures.
Thus, its mechanism involves:
Reducing excessive myosin-actin cross-bridges: This decreases the force of contraction, allowing the heart to relax more effectively.
Lowering left ventricular outflow tract (LVOT) obstruction: By reducing contractility, Mavacamten improves blood flow and reduces symptoms like shortness of breath and chest pain.
Enhancing diastolic function: It helps the heart fill more efficiently, improving overall cardiac output.
Preventing disease progression: Unlike beta-blockers or calcium channel blockers, which only manage symptoms, Mavacamten modifies the disease process by addressing the root cause of hypercontractility.
4. Pharmacokinetics
Absorption: Mavacamten is rapidly absorbed with an oral bioavailability of 85%. Meal timing does not affect its absorption, and the time to maximum concentration (Tmax) is 1 to 2 hours.
Distribution: The plasma protein binding of mavacamten is approximately 97%.
Metabolism: Mavacamten is primarily metabolized by CYP2C19 and, to a lesser extent, by CYP3A4. The accumulation of mavacamten is significantly influenced by CYP2C19 metabolism status, particularly, with the most pronounced accumulation occurring in patients who are poor metabolizers of CYP2C19.
Elimination: More than 80% of mavacamten is eliminated in urine. The mean elimination half-life is about 8 days.
5. Comparison with Other Treatments
Mavacamten is often compared to traditional HCM treatments:
Mavacamten stands out as the first targeted therapy for obstructive HCM, offering long-term benefits beyond symptom management. 6. Conclusion
Mavacamten represents a major breakthrough in the management of obstructive hypertrophic cardiomyopathy (oHCM) by directly targeting the underlying hypercontractility of the heart muscle. Unlike conventional treatments that focus on symptom relief, Mavacamten provides a disease-modifying approach, significantly improving cardiac function, quality of life, and reducing the need for invasive therapies like septal reduction surgery.
The drug’s mechanism of action, by inhibiting cardiac myosin, allows for a more controlled contraction, leading to improved blood flow and reduced left ventricular outflow tract (LVOT) obstruction. Clinical trials have demonstrated consistent efficacy, highlighting its superiority over traditional beta-blockers and calcium channel blockers.
While Mavacamten offers substantial benefits, careful monitoring is required to prevent heart failure complications, necessitating individualized dosing strategies. As research progresses, further studies may expand its application to non-obstructive HCM and other cardiac disorders.
Overall, Mavacamten has transformed the landscape of hypertrophic cardiomyopathy treatment, setting the foundation for future innovations in targeted cardiovascular therapy. 7. References
- BY Pranitha Acharya
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