Mavacamten Capsules (Camzyos)
June 30, 2022 4 minutes read
By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The FDA has approved a first-in-class, orally active, small molecule, selective allosteric inhibitor of cardiac myosin ATPase to treat obstructive hypertrophic cardiomyopathy (oHCM). Mavacamten received breakthrough and orphan status designations. It is distributed as Camzyos.
INDICATIONS
Mavacamten can be prescribed to adults with symptomatic New York Heart Association (NYHA) class II-III oHCM to improve functional capacity and symptoms.1
DOSAGE
The recommended starting dose is 5 mg daily given without regard to food.1 Initiation and titration is guided by left ventricular ejection fraction (LVEF) and Valsalva left ventricular outflow tract (LVOT) gradient. A detailed algorithm is provided in the prescribing information for interrupting, restarting, maintaining, and discontinuing treatment.1 Mavacamten is available as 2.5 mg, 5 mg, 10 mg, and 15 mg capsules.
POTENTIAL ADVANTAGES
Mavacamten is a first-in-class drug that can improve functional capacity and symptoms in patients with oHCM.1,2
POTENTIAL DISADVANTAGES
Mavacamten reduces systolic EF and may lead to heart failure caused by systolic dysfunction.1 The patient’s clinical status and LVEF should be assessed before and regularly during treatment. Concomitant use of drugs that reduce cardiac contractility should be avoided or closely monitored.
Mavacamten primarily is metabolized by CYP2C19 and (to a lesser extent) CYP3A4. Concomitant use with a moderate-to-strong CYP2C19 inhibitor or strong CYP3A4 inhibitor is contraindicated. Moderate or strong CYP2C19 and CYP3A4 inducers also are contraindicated. Mavacamten is an inducer of CYP3A4, CYP2C, and CYP2C19, and may lower plasma levels of substrates of these isoenzymes.
Based on animal data, mavacamten may cause fetal harm.1 Effective contraception should be used during and for four months after the last dose. Mavacamten is only available through the Camzyos REMS Program.
COMMENTS
Mavacamten reduces hypercontractility, a key pathogenesis of oHCM.3 The efficacy of mavacamten was evaluated in a double-blind, randomized, placebo-controlled study of adult subjects with symptomatic NYHA class II and III oHCM.1,2 These subjects had LVEF ≥ 55% and Valsalva LVOT peak gradient ≥ 50 mmHg at rest or with provocation. About three-quarters of subjects had NYHA class II symptoms. Most were on a beta-blocker (75%) or a calcium channel blocker (17%). Those on dual therapy of beta-blocker and calcium channel blocker as well as disopyramide or ranolazine were excluded. The remaining subjects were randomized to either mavacamten (starting at a dose of 5 mg; n = 123) or placebo (n = 128) for 30 weeks. The dose was adjusted based on response (decrease in LVOT gradient < 30 mmHg, maintaining LVEF ≥ 50%), and plasma level between 350 ng/mL and 700 ng/mL). The primary outcome endpoint (designated as responders) was a composite of a 1.5 mgL/kg/min or greater increase in peak oxygen consumption (pVO2) and at least one NYHA class reduction or a 3.0 mL/kg/min or greater increase in pVO2 and no worsening of NYHA class. Secondary endpoints included post-exercise LVOT gradients, pVO2, and change in NYHA class.
Proportion responders were 37% in the mavacamten group vs. 17% for placebo (P < 0.001). Sixty-five percent in the mavacamten group showed ≥ 1 class improvement in NYHA vs. 31% for placebo (P < 0.0001). Post-exercise mean (SD) change from baseline was -47 (40) mmHg for LVOT gradient and +1.4 (3.1) mL/kg/min for pVO2 for mavacamten vs. -10 (30) mmHg and -0.1 (3.0) mL/kg/min for placebo, respectively. The most common (vs. placebo) adverse reactions were dizziness (27% vs. 18%) and syncope (6% vs. 2%).1
CLINICAL IMPLICATIONS
It is rare to see oHCM, a heterogeneous genetic sarcomeric mutation disease caused by thickening of the heart muscle, mostly the septum, resulting in obstruction of blood flow from the heart.4 In patients with symptomatic oHCM with LV outflow obstruction, pharmacologic treatment recommended by the 2020 American Heart Association/American College of Cardiology HCM guidelines starts with nonvasodilating beta-blockers.5 If ineffective or not tolerated, non-dihydropyridine calcium channel blockers (verapamil, diltiazem) may be recommended. If still ineffective, the addition of disopyramide is recommended. Mavacamten offers another option and has shown effectiveness in patients previously treated with beta-blockers or calcium channel antagonists. Surgical approaches include septal reduction therapy with surgical myectomy or alcohol septal ablation.5 The long-term safety and whether mavacamten can reduce the need or likelihood of future surgery have not been established. Early phase II study evidence suggested mavacamten may not benefit patients with nonobstructive HCM.3,6 The drug is expected to cost $89,500 for one year of treatment despite the Institute for Clinical and Economic Review’s recommendation of $12,000-$15,000.7
REFERENCES
- MyoKardia, Inc. Camzyos prescribing information. April 2022.
- Olivotto I, Oreziak A, Barriales-Villa R, et al. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2020;396:759-769.
- Tower-Rader A, Ramchand J, Nissen SE, Desai MY. Mavacamten: A novel small molecule modulator of beta-cardiac myosin for treatment of hypertrophic cardiomyopathy. Expert Opin Investig Drugs 2020;29:1171-1178.
- U.S. Food & Drug Administration. FDA approves new drug to improve heart function in adults with rare heart condition. Content current as of April 29, 2022. https://bit.ly/3PU31Af
- Ommen SR, Mital S, Burke MA, et al. 2020 AHA/ACC guideline for the diagnosis and treatment of patients with hypertrophic cardiomyopathy: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol 2020;76:e159-e240.
- Ho CY, Mealiffe ME, Bach RG, et al. Evaluation of mavacamten in symptomatic patients with nonobstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 75:2649-2660.
- Institute for Clinical and Economic Review. Hypertrophic cardiomyopathy. An assessment of mavacamten. October 2021.
Mavacamten can be prescribed to adults with symptomatic New York Heart Association class II-III obstructive hypertrophic cardiomyopathy to improve functional capacity and symptoms.
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