Pharmacological Profile of Mavacamten and Key Studies of Its Use in HCM Treatment
A new addition to the treatment options for hypertrophic cardiomyopathy, approved for use in European Union countries in June 2023, is the selective reversible cardiac myosin inhibitor mavacamten. The following review summarizes its fundamental pharmacological characteristics along with the results of several crucial clinical studies and highlights the potential integration of mavacamten into clinical practice.
Introduction
Hypertrophic cardiomyopathy (HCM) is a condition characterized by left ventricular hypertrophy that is not caused by common cardiac or systemic reasons. The hypertrophy most commonly affects the basal part of the interventricular septum and, in most cases, causes outflow tract obstruction of the left ventricle (LVOT). Typical symptoms include chest pain on exertion, shortness of breath, and syncope.
Previous treatment options included beta-blockers, calcium channel blockers, or disopyramide. The cardiac myosin inhibitor mavacamten has recently demonstrated significant symptom relief in clinical trials, leading to the potential postponement of invasive treatments for patients.
Mechanism of Action and Effect of Mavacamten
Hypercontractility and impaired myocardial relaxation play a central role in the pathophysiology of HCM. These are caused by excessive formation of systolic and residual diastolic cross-bridges during contraction, resulting from disturbances in myosin activation and inactivation. Normally, 40–50% of myosin heads remain inactive, whereas in HCM it is only 15–20%.
Mavacamten selectively and reversibly inhibits beta-cardiac myosin ATPase, thereby modulating the number of contractile myosin heads and reducing the likelihood of excessive cross-bridge formation. Mavacamten induces an energy-saving, super-relaxed state of myosin that can be readily activated if needed.
At the start of treatment, there is a dose-dependent reversible decrease in left ventricular ejection fraction (LVEF). It is recommended to initiate treatment with caution due to the risk of heart failure, and the drug is not recommended for patients with LVEF < 55%. If LVEF drops below 50% during treatment, a 4-week drug discontinuation is advised.
Pharmacokinetic Characteristics
Oral mavacamten has excellent bioavailability (approximately 85%) and rapid absorption, with maximum plasma concentration reached on average within 1 hour (range: 0.5–3 hours). The drug has a high distribution volume and a long elimination phase. The terminal half-life is estimated to be 6 days for ultra-rapid CYP2C19 metabolizers, 8 days for rapid metabolizers, and 10 days for intermediate metabolizers. For poor metabolizers, it can be up to 23 days. Therefore, dose adjustment is recommended in such cases due to the risk of accumulation.
Key Clinical Studies
PIONEER-HCM
An open-label phase II study evaluated the efficacy of mavacamten in 21 patients with symptomatic HCM and LVOT obstruction. The primary endpoint was the reduction of LVOT gradient after exercise. Patients were randomized 1:1 and followed for 12 weeks. In arm A, participants discontinued other therapies at least 14 days before starting mavacamten, while in arm B, they continued their usual treatment (beta-blockers).
The initial daily dose of mavacamten in arm A was 10 or 15 mg (depending on weight). In arm B, treatment started at 2 mg daily, with possible titration at week 4. After 12 weeks of treatment, LVOT gradient decreased by 90 mmHg (p = 0.008 from baseline) in arm A, while in arm B, it decreased by 25 mmHg (p = 0.02 from baseline). Additionally, there was an increase in partial pressure of oxygen in venous blood (pVO2), a reduction in resting LVOT gradient and gradient after Valsalva maneuver, and improvement in NYHA score.
20 patients remained on treatment for 12 weeks, with 1 participant in arm A discontinuing treatment due to atrial fibrillation recurrence requiring hospitalization. Atrial fibrillation occurred in a total of 5 patients, and transient reduction in LVEF was observed in 3 patients.
EXPLORER-HCM
A randomized double-blind placebo-controlled phase III study examined the effect of mavacamten in 251 symptomatic patients with HCM and LVOT obstruction. Participants were randomized 1:1 to receive mavacamten at a dose of 2.5–15 mg daily or placebo for 30 weeks.
Treatment with mavacamten resulted in a reduction of LVOT obstruction, increased exercise capacity, and improvement in NYHA functional class by > 1 class. In the mavacamten arm, pVO2 increased by ≥ 1.5 ml/kg/min and NYHA improved by ≥ 1 class or pVO2 increased by > 3.0 ml/kg/min without NYHA worsening in 37% of patients compared to 17% in the placebo arm (p = 0.0005).
Seven patients experienced a transient reduction in LVEF to < 50%. Incidence of atrial fibrillation was similar in both arms.
VALOR-HCM
The VALOR-HCM study yielded interesting results, comparing mavacamten (2.5–15 mg daily) to placebo over 16 weeks in 112 patients recommended for septal reduction therapy (SRT).
By the end of the study, SRT was still suitable for 18% of patients in the mavacamten arm compared to 77% in the placebo arm (p < 0.0001). There was also a reduction in post-exercise LVOT gradient by 37 mmHg and improvement in NYHA by ≥ 1 class in 41% of patients.
Two patients receiving mavacamten experienced a reduction in LVEF to < 50%, which resolved after a 4-week drug discontinuation.
Mavacamten in Practice
Mavacamten is currently approved in the form of oral capsules of various strengths (2.5 mg, 5 mg, 10 mg, 15 mg) for the treatment of symptomatic obstructive HCM in adult patients with NYHA class II–III. Most participants of the aforementioned studies took the typical HCM treatment concurrently with mavacamten.
Conclusion
Since obstructive cardiomyopathy is one of the risk factors for sudden cardiac death, it is crucial not to underestimate its diagnosis and treatment. Mavacamten, as a selective myosin ATPase inhibitor, normalizes the actin-myosin binding, thereby reducing contractility and improving myocardial energetics.
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Sources:
1. Dong T., Alencherry B., Ospina S., Desay M. Y. Review of mavacamten for obstructive hypertrophic cardiomyopathy and future directions. Drug Des Devel Ther 2023; 17: 1097–1106, doi: 10.2147/DDDT.S368590.
2. EPAR Camzyos. European Medicines Agency, 2023 Jul 24. Available at: www.ema.europa.eu/en/medicines/human/EPAR/camzyos#:~:text=Camzyos%20received%20a%20marketing%20authorisation,EU%20on%2026%20June%202023
3. SPC Camzyos. Available at: www.ema.europa.eu/en/documents/product-information/camzyos-epar-product-information_cs.pdf
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