Mavacamten for symptomatic hypertrophic obstructive cardiomyopathy

Mavacamten for symptomatic hypertrophic obstructive cardiomyopathy

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

introduction

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

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

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

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

Evidence showed a reduction in biomarkers, including heart wall stress, hypercontractility, diastolic compliance, and left ventricular outflow tract gradients.

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

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

At the conclusion of the study, 45 of the 123 patients who received mavacamten therapy successfully achieved primary endpoints, which included increased peak oxygen uptake (pVO2) and improved NYHA class. Compared to placebo, patients taking mavacamten also showed significant improvement in exercise capacity, symptoms and quality of life.

According to data presented at the American College of Cardiology 2022 Scientific Sessions, 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 levels. (NT-proBNP). .

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

More than 200 patients remained in the study for more than 48 weeks and 67 patients reached 84 weeks. Clinically significant 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 long-term follow-up. Exposure-adjusted event rates were also stable or lower in this cohort.

All participants in the EXPLORER-LTE cohort initiated therapy with mavacamten 5 mg daily and dose adjustments were made at weeks 4, 8 and 12 based on echocardiographic measurements of Valsalva’s LVOT gradient and left ventricular ejection fraction. . Dose adjustment was also possible at week 24 after echocardiographic assessment of the LVOT gradient after exercise.

Mechanism of action

Mavacamten is a first-class 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 cardiac contraction force and promotes diastolic relaxation, thereby minimizing hypercontractility in oHCM.4

In vivo studies in mice show evidence of reduced cardiac myosin sarcomere output power.5 Further 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 strong bioavailability. Regarding the major pathways, mavacamten is mainly metabolised by CYP2C19 and 3A4 in all species.

Dosage and administration

Mavacamten is administered orally. EXPLORER-CM participants who received mavacamten therapy started at 5 mg per day.3 Providers may need to routinely adjust the dose for patients if they prescribe this drug.

At weeks 8 and 14, the researchers administered an individualized dosage of 2.5 mg to 15 mg, based on plasma drug concentrations and decreased LVOT. The target plasma concentration of mavacamten ranges from 350 to 500 ng / mL. Laboratories performed regular patient assessments every 2-4 weeks for the remainder of the 30-week treatment cycle to adjust the dosage accordingly.

Adverse Events (AE)

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

8% of patients who finished mavacamten treatment experienced at least 1 serious adverse event, 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 adverse event.

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

Warnings and Precautions

Providers should take precautions when recommending mavacamten in patients who meet the exclusion criteria for EXPLORER-CM.

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

Patients with a QT interval greater than 500 milliseconds, corrected by Fridericia’s formula, were excluded from the study. Providers should exercise caution in patients with high baseline values ​​or those taking QT interval prolonging agents.

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

Pregnancy and breastfeeding

Pregnant or lactating female patients were not included in the EXPLORER-CM study. There are no data on the presence of mavacamten in breast milk. Avoid use in these populations due to limited data on potential harm to the fetus or neonate.

About the author

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

References

  1. Bristol Myers Squibb announces positive topline results from the phase 3 valor-HCM study 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-hypertrophic-obstructive-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, 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., … Researchers from the EXPLORER-HCM study (2020). Mavacamten for the treatment of symptomatic hypertrophic obstructive cardiomyopathy (EXPLORER-HCM): a randomized, double-blind, placebo-controlled, phase 3 study. 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.
  4. Kazmierczak, K., Szczesna-Cordary, D. and Tanner, B. (2021). Mavacamten reduces maximal strength and sensitivity to Ca2 + in the mouse model of N47K-myosin regulatory light chain hypertrophic cardiomyopathy. American journal of physiology. Cardiac and circulatory physiology, 320(2), H881 – H890. https://doi.org/10.1152/ajpheart.00345.2020
  5. 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-class allosteric small molecule modulator of cardiac myosin beta. xenobiotics, 49(6), 718-733.

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