Mavacamten for symptomatic obstructive hypertrophic cardiomyopathy
Mavacamten is a first-in-class selective allosteric modulator of cardiac myosin beta ATPase for the treatment of symptomatic hypertrophic obstructive cardiomyopathy.
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 the thickened walls of the heart muscle.1
Symptomatic oHCM is a chronic condition characterized by an enlarged, undilated left ventricle leading to hypercontractility of the heart and poor blood flow to the affected lobe.2 This cardiac enlargement is usually the result of a genetic mutation in the contractile myofilaments of the 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 with hypertrophic cardiomyopathy have ventricular outflow tract obstruction due to excess muscle tissue. oHCM is associated with atrial fibrillation, stroke, heart failure, and sudden cardiac death.
Evidence showed a reduction in 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 evaluating the efficacy and safety of mavacamten.3
The researchers recruited 251 patients with a left ventricular outflow tract (LVOT) gradient of at least 50 mmHg enrolled to receive mavacamten or placebo. The researchers monitored the patients every 2 to 4 weeks for a total of 30 weeks.
At the end of the trial, 45 of 123 patients receiving mavacamten treatment successfully achieved primary endpoints, which included increased maximal oxygen uptake (pVO2) and improved class NYHA. 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 long-lasting improvement in LVOT gradients, as well as levels of NYHA-class and N-terminal pro brain natriuretic peptide (NT-proBNP), according to data presented during the sessions. American College of Cardiology 2022 Scientists.
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 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 maintained 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. Exposure-adjusted event rates were also stable or lower in this cohort.
All participants in the EXPLORER-LTE cohort started treatment with 5 mg mavacamten daily and dose adjustments were made at weeks 4, 8 and 12 based on echocardiographic measurements of the Valsalva LVOT gradient and fraction d ventricular ejection. Dose adjustment was also possible at week 24 after onsite echocardiographic assessment of the LVOT gradient after exercise.
Mavacamten is a first-order selective allosteric modulator of cardiac myosin beta ATPase. The drug acts on the sarcomere to inhibit the formation of myosin-actin cross-bridges.1 Inhibition of cardiac myosin reduces the force of cardiac contraction and promotes diastolic relaxation, thereby minimizing hypercontractility in oHCM.4
In-vivo studies in mice show evidence of reduced cardiac myosin sarcomere output.5 Additional studies in rats, dogs and monkeys estimate human pharmacokinetics and reveal metabolic pathways.
Research suggests low clearance, high volume of distribution, long half-life and high bioavailability. Regarding major pathways, mavacamten is primarily metabolized by CYP2C19 and 3A4 across species.
Dosage and direction
Mavacamten is administered orally. EXPLORER-CM participants receiving mavacamten treatment started at 5 mg daily.3 Providers may need to adjust the dose regularly for patients if they prescribe this medication.
At weeks 8 and 14, researchers administered individualized doses ranging from 2.5 mg to 15 mg, depending on plasma drug concentrations and reduction in LVOT. The target plasma concentration of mavacamten ranges from 350 to 500 ng/mL. The laboratories performed regular patient assessments every 2-4 weeks for the remainder of the 30-week treatment to adjust the dosage accordingly.
Adverse Events (AE)
AEs reported during EXPLORER-CM were mild to moderate. The study shows that mavacamten is 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 who received mavacamten experienced atrial fibrillation and syncope, and 1 patient on placebo suffered sudden death.
Eight percent of patients who completed treatment with mavacamten experienced at least 1 serious AE, including atrial fibrillation, syncope, exercise cardiomyopathy, diverticulitis, infection, contusion or fracture of the forearm. arm ; 9% of patients in the placebo group also reported at least 1 serious AE.
No changes in laboratory values, electrocardiographs and vital signs, including resting heart rate and blood pressure, were observed in patients at the end of treatment with mavacamten.
Warnings and Precautions
Providers should exercise caution in recommending mavacamten in patients who met the exclusion criteria for EXPLORER-CM.
Patients included in the Phase 3 trial continued to receive hypertrophic cardiomyopathy therapies, including beta-blockers and non-dihydropyridine calcium channel blockers.3 However, the use of disopyramide has been excluded. Additional data are needed to determine the safety of concomitant use of mavacamten and disopyramide.
Patients with a QT interval greater than 500 milliseconds, corrected with Fridericia’s formula, were excluded from the trial. Providers should exercise caution in patients with high baseline values or in those taking QT-prolonging agents.
Other considerations for exclusion criteria include a history of syncope, sustained exercise ventricular tachyarrhythmia, and paroxysmal or intermittent atrial fibrillation. There are currently insufficient data to recommend the use of mavacamten in children as the patients included in the study were at least 18 years old.
Pregnancy and breast feeding
Pregnant or breastfeeding patients were not included in the EXPLORER-CM trial. There are no data regarding the presence of mavacamten in breast milk. Avoid use in these populations due to limited data on potential harm to the fetus or infant.
About the Author
Victoria Fal is a 2024 PharmD candidate at the University of Connecticut.
- Bristol Myers Squibb announces positive topline results from the Phase 3 valor-HCM trial, evaluating Mavacamten in patients with hypertrophic obstructive cardiomyopathy 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
- DynaMed. Hypertrophic cardiomyopathy. EBSCO Information Services. Accessed March 9, 2022. https://www.dynamed.com/condition/hypertrophic-cardiomyopathy
- Olivotto, I., Oreziak, A., Barriales-Villa, R., Abraham, TP, Masri, A., Garcia-Pavia, P., Saberi, S., Lakdawala, NK, Wheeler, MT, Owens, A. , Kubanek, M., Wojakowski, W., Jensen, MK, Gimeno-Blanes, J., Afshar, K., Myers, J., Hegde, SM, Solomon, SD, Sehnert, AJ, Zhang, D., … Investigators of the EXPLORER-HCM study (2020). Mavacamten for the treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomized, 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, PO, Watanabe, M., Bishaw, Y., Huckabee, AM, Agonias, KB, 4. 4.
- Kazmierczak, K., Szczesna-Cordary, D. and Tanner, B. (2021). Mavacamten decreases maximal strength and Ca2+ sensitivity in the N47K-myosin regulatory light chain mouse model of hypertrophic cardiomyopathy. American Journal of Physiology. Cardiac and circulatory physiology, 320(2), H881–H890. https://doi.org/10.1152/ajphead.00345.2020
- Grillo, MP, Erve, JC, Dick, R., Driscoll, JP, 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 cardiac myosin beta. Xenobiotic, 49(6), 718-733.