Clinical Overview: Mavacamten for Symptomatic Obstructive Hypertrophic Cardiomyopathy

Mavacamten is a first-in-class selective allosteric modulator of beta cardiac myosin ATPase for the treatment of symptomatic obstructive hypertrophic cardiomyopathy.

Introduction

Mavacamten (Camzyos) is an oral medication recently approved by the FDA for the treatment of adult patients with symptomatic New York Heart Association (NYHA) class II-III obstructive hypertrophic cardiomyopathy (oHCM). The drug is an allosteric modulator of cardiac myosin, targeting thickened heart muscle walls.1

Symptomatic oHCM is a chronic disease characterized by an enlarged, nondilated left ventricle resulting in hypercontractility of the heart and improper blood circulation of the affected lobe.2 This cardiac hypertrophy is commonly a result of genetic mutation in the contractile myofilaments of heart muscle, rather than a complication of systemic or cardiac disease.

Due to its hereditary nature, this disease can affect both children and adults. If symptomatic, patients may experience chest pain, dyspnea, syncope, or palpitations.

Seventy percent of patients who suffer with hypertrophic cardiomyopathy experience ventricular outflow tract obstruction due to the excessive muscle tissue. oHCM is associated with atrial fibrillation, stroke, heart failure, and sudden cardiac death.

Evidence has shown reduction of biomarkers, including cardiac wall stress, hypercontractility, diastolic compliance, and left ventricular outflow tract gradients.

EXPLORER-HCM was a randomized, double-blind, placebo-controlled, phase 3 trial that assessed efficacy and safety of mavacamten.3

The researchers enrolled 251 patients with left ventricular output tract (LVOT) gradient of at least 50 mmHg enrolled to receive mavacamten or placebo. Researchers monitored patients every 2 to 4 weeks for a total of 30 weeks.

At the conclusion of the trial, 45 of the 123 patients receiving mavacamten therapy successfully met primary endpoints, which included increase in peak oxygen consumption (pVO2) and improvement in NYHA class. Compared to placebo, patients taking mavacamten also showed significant improvement in exercise capacity, symptoms, and quality of life.

The EXPLORER-LTE study found that treatment with mavacamten provides sustained improvement in LVOT gradients, as well as NYHA Class and N-terminal pro brain natriuretic peptide (NT-proBNP) levels, according to data presented at the American College of Cardiology 2022 Scientific Sessions.

The EXPLORER-LTE trial included a cohort of the MAVA-LTE study, the largest and longest evaluation of mavacamten in patients with symptomatic oHCM. EXPLORER-LTE enrolled 231 of the 244 patients who were eligible for the long-term extension study at the end of EXPLORER-HCM.

More than 200 patients remained on study for more than 48 weeks and 67 patients reached 84 weeks. Clinically meaningful improvements were sustained in LVOT gradients, NYHA Class, and NT-proBNP levels at 48 weeks and up to 84 weeks.

The safety profile remained consistent with EXPLORER-HCM and no new safety signals were observed during longer term follow-up. The exposure-adjusted event rates were also stable or lower in this cohort.

All participants in the EXPLORER-LTE cohort started therapy on 5 mg of mavacamten daily and dose adjustments were made at weeks 4, 8, and 12 based on echocardiography measures of Valsalva LVOT gradient and left ventricular ejection fraction. Dose adjustment was also possible at week 24 following site-read echocardiography assessment of LVOT gradient after exercise.

Mechanism of Action

Mavacamten is a first-in-class selective allosteric modulator of beta cardiac myosin ATPase. The medication acts on the sarcomere to inhibit myosin-actin cross bridge formation.1 Inhibition of cardiac myosin reduces force of cardiac contraction and promotes diastolic relaxation, thus minimizing hypercontractility in oHCM.4

In-vivo studies in mice show evidence of reduced cardiac myosin sarcomere power output.5 Additional studies performed in rats, dogs, and monkeys estimate human pharmacokinetics and reveal metabolic pathways.

The research suggests low clearance, high volume of distribution, long half-life, and strong bioavailability. Regarding major pathways, mavacamten is primarily metabolized by CYP2C19 and 3A4 across species.

Dosage and Administration

Mavacamten is administered orally. EXPLORER-CM participants receiving mavacamten therapy began at 5 mg daily.3 Providers may need to dose-adjust routinely for patients if prescribing this medication.

At weeks 8 and 14, researchers administered individualized dosing ranging from 2.5 mg to 15 mg, based upon drug plasma concentrations and reduction in LVOT. Target mavacamten plasma concentration ranges from 350-500 ng/mL. Laboratories performed regular evaluations of patients every 2 to 4 weeks for the rest of the 30-week treatment course to adjust dosing accordingly.

Adverse Events (AEs)

AEs reported during EXPLORER-CM were mild to moderate. The study shows mavacamten to be generally well tolerated, with 97% of patients completing the trial with a total of 5 withdrawals.3 Three patients withdrew from the trial due to AEs. Two patients administered mavacamten experienced atrial fibrillation and syncope, and 1 placebo patient suffered sudden death.

Eight percent of patients who finished mavacamten treatment experienced at least 1 serious AE, including atrial fibrillation, syncope, stress cardiomyopathy, diverticulitis, infection, contusion, or forearm fracture; 9% of patients in the placebo group also reported at least 1 serious AE.

No changes in laboratory values, electrocardiographs, and vital signs including, heart rate and blood pressure at rest, were observed in patients at the end of the mavacamten treatment.

Warnings and Precautions

Providers must take precaution in recommending mavacamten in patients who met that exclusion criteria for EXPLORER-CM.

Patients enrolled in the phase 3 trial continued to receive hypertrophic cardiomyopathy therapies, including beta-blockers and non-dihydropyridine calcium channel blockers.3 However, use of disopyramide was excluded. Further data are needed to determine the safety of concomitant use of mavacamten and disopyramide therapy.

Patients with a QT-interval more than 500 milliseconds, corrected with Fridericia’s formula, were excluded from the trial. Providers should practice caution in patients with elevated baselines or those taking QT-prolonging agents.

Other considerations regarding exclusion criteria include history of syncope, sustained ventricular tachyarrhythmia with exercise, and paroxysmal or intermittent atrial fibrillation. There are currently insufficient data to recommend use of mavacamten in children as patients enrolled in the study were at least 18 years of age.

Pregnancy and Lactation

Female patients who were pregnant or lactating were not included in EXPLORER-CM trial. There is no data regarding presence of mavacamten in breast milk. Avoid use in these populations due to limited data on potential harm to fetus or infant.

About the Author

Victoria Fal is a 2024 PharmD candidate at the University of Connecticut.

References

  1. Bristol Myers Squibb announces positive topline results from phase 3 valor-HCM trial, evaluating Mavacamten in patients with obstructive hypertrophic cardiomyopathy who are eligible for septal reduction therapy. Bristol Meyers Squibb. (2022, February 16). Retrieved March 9, 2022, from https://news.bms.com/news/details/2022/Bristol-Myers-Squibb-Announces-Positive-Topline-Results-from-Phase-3-VALOR-HCM-Trial-Evaluating-Mavacamten-in-Patients-with-Obstructive-Hypertrophic-Cardiomyopathy-Who-are-Eligible-for-Septal-Reduction-Therapy/default.aspx
  2. DynaMed. Hypertrophic Cardiomyopathy. EBSCO Information Services. Accessed March 9, 2022. https://www.dynamed.com/condition/hypertrophic-cardiomyopathy
  3. Olivotto, I., Oreziak, A., Barriales-Villa, R., Abraham, T. P., Masri, A., Garcia-Pavia, P., Saberi, S., Lakdawala, N. K., Wheeler, M. T., Owens, A., Kubanek, M., Wojakowski, W., Jensen, M. K., Gimeno-Blanes, J., Afshar, K., Myers, J., Hegde, S. M., Solomon, S. D., Sehnert, A. J., Zhang, D., … EXPLORER-HCM study investigators (2020). Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet (London, England)396(10253), 759–769.https://doi.org/10.1016/S0140-6736(20)31792-X Awinda, P. O., Watanabe, M., Bishaw, Y., Huckabee, A. M., Agonias, K. B., 4. 4.
  4. Kazmierczak, K., Szczesna-Cordary, D., & Tanner, B. (2021). Mavacamten decreases maximal force and Ca2+ sensitivity in the N47K-myosin regulatory light chain mouse model of hypertrophic cardiomyopathy. American journal of physiology. Heart and circulatory physiology320(2), H881–H890. https://doi.org/10.1152/ajpheart.00345.2020
  5. Grillo, M. P., Erve, J. C., Dick, R., Driscoll, J. P., Haste, N., Markova, S., ... & Evanchik, M. (2019). In vitro and in vivo pharmacokinetic characterization of mavacamten, a first-in-class small molecule allosteric modulator of beta cardiac myosin. Xenobiotica49(6), 718-733.