MAVACAMTEN: A breakthrough in the management of obstructive hypertrophic cardiomyopathy
- Greeshma
- Jul 2
- 5 min read
Introduction
Mavacamten (brand name Camzyos) is a first-in-class, selective cardiac myosin inhibitor developed for hypertrophic cardiomyopathy (HCM). It directly targets the hypercontractile sarcomeric phenotype that underlies HCM. In January 2022 the U.S. FDA approved mavacamten for adults with symptomatic (NYHA class II–III) obstructive HCM (oHCM) to improve functional capacity and symptoms. This represented a major advance by addressing the disease mechanism rather than only symptom relief. In Phase 2 and 3 trials of oHCM, mavacamten was well tolerated and produced substantial reductions in left ventricular outflow tract (LVOT) gradients, improvements in exercise capacity, symptoms, patient-reported health status, and biomarkers .Notably, imaging studies also suggested favorable cardiac remodeling with chronic use. Mavacamten’s approval in HCM reflects a precision-medicine approach, exploiting the genetic and molecular basis of the disease .
Mechanism of Action
At the molecular level, mavacamten is a selective, reversible allosteric inhibitor of β-cardiac myosin ATPase . It binds to cardiac myosin and reduces the probability that myosin heads enter the force-generating state. Preclinical studies show mavacamten shifts the myosin population toward an energy-sparing “super-relaxed” off state, thereby decreasing excess cross-bridge formation . By normalizing the ratio of active to relaxed myosin heads, mavacamten attenuates sarcomeric hyperactivity. The net effect is reduced myocardial contractility and a lowering of LVOT gradients in oHCM . This mechanism is fundamentally different from beta-blockers or calcium-channel blockers: mavacamten directly targets the dysfunctional sarcomere. In vivo, these effects translate into lower LVOT obstruction and improved ventricular relaxation and filling .
Clinical Trial Data
Key evidence for mavacamten comes from controlled trials in oHCM:
• EXPLORER-HCM (Phase 3): This double-blind, placebo-controlled trial randomized 251 patients with symptomatic oHCM to mavacamten (5 mg daily, titrated to target) or placebo for 30 weeks . The composite primary endpoint was a combination of improvements in peak VO₂ and NYHA class. 37% of mavacamten-treated patients met the primary endpoint versus 17% on placebo (p=0.0005) . Mavacamten also produced larger reductions in LVOT gradients and greater gains in exercise capacity . Patient-reported outcomes improved: e.g. the Kansas City Cardiomyopathy Questionnaire (KCCQ) summary score increased by ~9 points more on mavacamten than placebo. These results established that mavacamten significantly relieves obstruction and symptoms in oHCM.
• VALOR-HCM (Phase 3): This trial enrolled 112 patients with severe obstructive HCM already referred for septal reduction (surgery or ablation). Patients received mavacamten or placebo for 16 weeks. The primary endpoint was a composite reflecting avoidance of septal reduction: patients who no longer met invasive-therapy criteria or chose to defer surgery. Mavacamten had a dramatic effect: 82% of treated patients were no longer eligible for or decided against septal reduction by Week 16, versus only 23% on placebo . In absolute terms, only 17.9% of mavacamten patients vs 76.8% of placebo patients proceeded with or remained eligible for septal reduction (p<0.0001) . Mavacamten also met all key secondary endpoints, significantly improving resting and exercise LVOT gradients, NYHA class, KCCQ symptom scores, NT-proBNP, and troponin I levels compared to placebo . This trial demonstrated that mavacamten can defer or eliminate the need for invasive surgery in many refractory oHCM patients.
• Other trials: Phase 2 studies confirmed these findings. In PIONEER-HCM (n≈21, 12 weeks), mavacamten markedly reduced LVOT gradients and improved exercise parameters. Longer-term extension data (PIONEER-OLE) showed durable gradient reductions over 48+ weeks. These early trials guided the dosing and safety monitoring used in EXPLORER/VALOR . The consistent theme across trials is a tolerable safety profile and robust hemodynamic benefit in oHCM.
Approved Clinical Uses
Mavacamten is approved only for obstructive HCM. The U.S. indication (and a similar EMA approval in 2023) is adult patients with symptomatic (NYHA II–III) oHCM to improve exercise capacity and symptoms . In practice, this applies to patients with significant dynamic LVOT gradients (typically ≥50 mmHg at rest or with provocation) despite standard therapy. Mavacamten is not approved for nonobstructive HCM or heart failure outside this setting . It is available in capsule form (2.5, 5, 10, 15 mg) and, due to its novel mechanism and risks, is distributed under a Risk Evaluation and Mitigation Strategy (REMS) program . As of late 2023, mavacamten/Camzyos has also been approved or authorized in Europe and over 50 countries worldwide for the same indication .
Dosage and Administration
Mavacamten is given orally once daily as 5 mg capsules, with dose titration guided by echocardiographic monitoring. The recommended initial dose is 5 mg once daily (with or without food) . Depending on response and safety parameters, the dose may be adjusted in 2.5 mg increments to 2.5, 5, 10, or 15 mg daily (maximum 15 mg) . Treatment is initiated only in patients with a baseline LVEF ≥55%. At each dose evaluation (typically every 12 weeks during maintenance, or more frequently during initial titration), both LVEF and LVOT gradient (by Valsalva or exercise) are assessed. The goal is to reduce LVOT obstruction while keeping LVEF ≥50% . If LVEF falls below 50% or significant heart failure symptoms occur, mavacamten is interrupted or dose-reduced per protocol. In practice, patients are closely monitored with echocardiograms at baseline, week 4, 8, and 12 during initiation, then every 12 weeks or so during maintenance . Pharmacokinetic variability (especially CYP2C19 metabolism) means titration schedules may vary. Because of its complexity and risks, mavacamten is dispensed under a specialized REMS program requiring prescriber and pharmacy certification .
Safety and Side Effects
Mavacamten’s safety profile reflects its negative inotropic action. It carries a boxed warning for heart failure due to systolic dysfunction . Before and during therapy, left ventricular function must be carefully monitored. The most common adverse reactions (incidence ≥5% and greater than placebo) in clinical trials were dizziness (27% on mavacamten vs 18% on placebo) and syncope (6% vs 2%) . Other frequent events included headache, nausea, and fatigue; dyspnea was reported more often on drug (≈12% vs 9% placebo) . Importantly, some patients experienced reductions in LVEF. In EXPLORER-HCM, 6% of mavacamten-treated patients had transient LVEF drop below 50% (median ~48%); all recovered after treatment interruption . Any LVEF decline requires prompt dose adjustment or holding therapy.
Contraindications include baseline LVEF <50% and use of strong or moderate CYP2C19 or CYP3A4 modulators which markedly alter mavacamten levels. For example, strong CYP2C19 inhibitors or inducers are contraindicated due to risk of excessive or inadequate exposure. Mavacamten can interact with other negative inotropes (e.g. disopyramide, verapamil, ranolazine with beta-blockers) and should be avoided with these combinations . Pregnancy is contraindicated given animal studies showing fetal harm ; effective contraception is required for women of reproductive potential . Finally, because of the heart-failure risk, mavacamten is available only through the Camzyos REMS program, which mandates patient enrollment and echo monitoring .
Conclusion
Mavacamten is the first targeted therapy for obstructive HCM and represents a landmark shift toward precision cardiology in this disease. By directly modulating sarcomeric myosin activity, it reduces LVOT obstruction and improves symptoms and exercise capacity, as shown in EXPLORER-HCM and VALOR-HCM . Its introduction has provided an alternative to invasive septal reduction for many patients. While it requires careful dosing and echocardiographic monitoring, mavacamten’s benefits in oHCM are clear. Ongoing research into other populations (nonobstructive HCM, HFpEF) and longer-term outcomes will further clarify its potential. As of now, mavacamten has had a major impact on HCM management and exemplifies how understanding disease mechanisms can lead to effective new therapies.
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