Mavacamten

Mavacamten (brand name Camzyos) is a first-in-class cardiac myosin inhibitor approved by the FDA in 2022. It is designed to target the underlying cause of obstructive hypertrophic cardiomyopathy by modulating the contractile function of heart muscle cells.

This medication is indicated for adults with symptomatic obstructive hypertrophic cardiomyopathy, characterized by abnormal thickening of the heart muscle that can lead to outflow obstruction, shortness of breath, chest pain, and exercise intolerance.

Mavacamten works by selectively inhibiting cardiac myosin ATPase activity, reducing excessive actin-myosin cross-bridge formation in cardiomyocytes. This mechanism decreases hypercontractility and improves ventricular filling and overall cardiac function.

The primary gene involved in mavacamten metabolism is CYP2C19, a member of the cytochrome P450 family of enzymes responsible for metabolizing many drugs in the liver. Variations in CYP2C19 can lead to differences in enzyme activity, classified into metabolizer phenotypes based on how quickly a person processes certain medications.

Individuals who carry genetic variants that reduce or enhance CYP2C19 function may experience altered mavacamten clearance. Poor metabolizers may have higher blood levels and a greater risk of adverse effects, whereas ultrarapid metabolizers may clear the drug more quickly, potentially reducing its effectiveness.

CYP2C19 metabolizer status influences mavacamten plasma concentrations and the risk of adverse cardiac events. Poor and intermediate metabolizers may accumulate higher drug levels, increasing potential toxicity, while ultrarapid and rapid metabolizers may have lower exposure, potentially diminishing efficacy. Normal metabolizers are expected to have standard responses.

Different CYP2C19 metabolizer phenotypes lead to predictable changes in drug exposure and clinical outcomes with mavacamten:

Ultrarapid Metabolizer

• Effect on drug levels: Standard plasma levels
• Clinical consequence: Expected normal therapeutic response
• Side effects: No increased adverse effects observed

Rapid Metabolizer

• Effect on drug levels: Standard plasma levels
• Clinical consequence: Expected normal therapeutic response
• Side effects: Typical side effect profile; no added risk

Normal Metabolizer

• Effect on drug levels: Standard plasma levels
• Clinical consequence: Standard efficacy and safety
• Side effects: As noted in the prescribing information

Intermediate Metabolizer

• Effect on drug levels: Increased plasma concentrations
• Clinical consequence: Potential higher risk of adverse reactions including heart failure
• Side effects: Elevated risk of heart failure; severity potentially serious; frequency not well established

Poor Metabolizer

• Effect on drug levels: Markedly increased plasma concentrations
• Clinical consequence: Higher risk of adverse cardiac events, including heart failure
• Side effects: Significant risk of heart failure; severity potentially serious; frequency not well established

Indeterminate/Not Available

• Effect on drug levels: Unknown
• Clinical consequence: No specific guidance; follow standard dosing with clinical monitoring
• Side effects: Not defined due to indeterminate genotype

CYP2C19 Dosing Guideline

Phenotype	Clinical Consequence	Guideline Recommendation
Ultrarapid Metabolizer	No known impact; standard exposure expected	Initiate standard starting dose (5 mg once daily), with individualized titration and monitoring per FDA labeling.
Rapid Metabolizer	No known impact; standard exposure expected	Initiate standard starting dose (5 mg once daily), with individualized titration and monitoring per FDA labeling.
Normal Metabolizer	Standard exposure and response	Initiate standard starting dose (5 mg once daily), with individualized titration and monitoring per FDA labeling.
Intermediate Metabolizer	Higher systemic concentrations; increased adverse reaction risk	Initiate standard starting dose, with individualized titration and monitoring per FDA labeling; no genotype‐based adjustment necessary.
Poor Metabolizer	Markedly higher systemic concentrations; elevated adverse reaction risk	Initiate standard starting dose, with individualized titration and monitoring per FDA labeling; no genotype‐based adjustment necessary.
Likely Intermediate Metabolizer	Higher systemic concentrations; increased adverse reaction risk	Initiate standard starting dose, with individualized titration and monitoring per FDA labeling; no genotype‐based adjustment necessary.
Likely Poor Metabolizer	Markedly higher systemic concentrations; elevated adverse reaction risk	Initiate standard starting dose, with individualized titration and monitoring per FDA labeling; no genotype‐based adjustment necessary.
Indeterminate	Unknown impact	Initiate standard starting dose per FDA labeling; monitor clinically.
Not available	Unknown impact	Initiate standard starting dose per FDA labeling; monitor clinically.

No alternative drugs are specified in the FDA pharmacogenetic guidance for mavacamten. Other management options for hypertrophic cardiomyopathy may include beta-blockers (e.g., metoprolol), calcium channel blockers (e.g., verapamil), disopyramide, or interventional procedures such as septal myectomy or alcohol septal ablation. These are examples and not medical advice.

• FDA – Table of Pharmacogenetic Associations