Mavacamten for symptomatic obstructive hypertrophic cardiomyopathy

Background:
Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disorder, characterised by left ventricular hypertrophy and hypercontractility without another cause such as hypertension. Many patients develop left ventricular outflow tract (LVOT) obstruction (obstructive HCM). Patients may be asymptomatic or experience dyspnoea, fatigue, chest pain, limited exercise capacity and syncope. Serious complications include heart failure and sudden cardiac death.¹

Management of obstructive HCM may include lifestyle modifications (e.g. avoiding competitive sports), drug therapy or, for severe disease, septal reduction procedures. To date, drug therapy has focused on symptomatic relief with the use of beta blockers, non-dihydropyridine calcium channel blockers, disopyramide and diuretics.^1,2 Mavacamten is the first specific treatment for obstructive HCM.

Mechanism of action:
Mavacamten is a selective, reversible inhibitor of cardiac myosin ATPase. It reduces cardiac hypercontractility and LVOT obstruction by reducing the probability of actin–myosin cross-bridge formation and by promoting an energy-sparing super relaxed state.³

Clinical trials:
Approval of mavacamten is primarily based on the EXPLORER-HCM study, a phase 3 trial that randomised adults with obstructive HCM (peak LVOT gradient of 50 mmHg or greater and NYHA class II or III symptoms) to receive mavacamten (n=123) or placebo (n=128) for 30 weeks. Almost all patients were taking drug therapy for HCM, mainly beta blockers. Patients with a left ventricular ejection fraction (LVEF) less than 55% were excluded, and treatment was temporarily discontinued if LVEF was less than 50% at any echocardiographic assessment. The primary endpoint was a composite measure of exercise capacity (peak oxygen consumption) and symptoms (improvement or no worsening in NYHA class).⁴

Forty-five patients (37%) on mavacamten met the primary endpoint compared with 22 patients (17%) on placebo. A benefit for mavacamten was also demonstrated for all secondary efficacy endpoints, including change in post-exercise LVOT gradient, patient-reported outcomes of health status, and cardiac biomarkers. An ongoing open-label extension study showed improvements in the LVOT gradient were sustained through to 180 weeks.⁵

In another phase 3 randomised placebo-controlled trial (VALOR-HCM) involving 112 patients with drug-refractory symptoms, mavacamten substantially reduced the proportion of patients eligible for septal reduction therapy at week 16 (18% in the mavacamten group versus 77% in the placebo group)⁶. This benefit was sustained in an ongoing open-label extension study at week 128.⁷

Adverse effects:
Adverse effects of mavacamten were generally mild, most commonly dizziness and fatigue.^4,6

Seven patients (5.7%) in EXPLORER-HCM and 2 patients (3.6%) in VALOR-HCM had a transient decrease in LVEF below 50%. Rates of LVEF below 50% were higher in the open-label extension studies – 8.7% in the EXPLORER-HCM cohort, all of whom recovered,⁵ and 13.9% in the VALOR-HCM cohort, including 2 patients who developed an LVEF of 30% or less, one of whom died.⁷

Dosage and administration:
The starting dose is 5 mg orally daily with titration up or down based on the LVOT gradient, LVEF and symptoms. The maximum dose is 15 mg daily.

Dose adjustment is not required for patients with mild or moderate hepatic or renal impairment. Mavacamten has not been studied in patients with severe hepatic or renal impairment.³

Precautions:
Mavacamten should not be initiated in patients with an LVEF less than 55%. Once the dose of mavacamten has been titrated for maintenance therapy, echocardiographic assessment should be undertaken every 12 weeks. LVEF should also be assessed if the patient’s clinical status changes or they experience a serious intercurrent illness such as infection or arrhythmia. If the patient’s LVEF is less than 50%, mavacamten should be withheld for at least 4 weeks and until LVEF returns to 50% or more, and restarted at a lower dose.

Mavacamten is extensively metabolised by cytochrome P450 (CYP) 2C19 and to a lesser extent CYP3A4. Use is contraindicated with moderate to strong inducers of CYP2C19 or CYP3A4, moderate to strong inhibitors of CYP2C19, and strong inhibitors of CYP3A4.

The risk of heart failure should also be considered with drugs that reduce cardiac contractility, such as beta blockers, diltiazem, verapamil or disopyramide.³ If treatment with a negative inotrope is initiated (or the dose is increased) in a patient receiving mavacamten, close review with echocardiographic monitoring of LVEF is recommended until stable doses and clinical response have been achieved.³

Use in pregnancy and breastfeeding:
Mavacamten should not be used in pregnant people based on animal studies showing a risk of fetal harm. It is classified as Therapeutic Goods Administration pregnancy category D. It is unknown whether mavacamten or its metabolites are excreted in human milk, but no adverse effects were observed in animal studies.³

Place in therapy:
Mavacamten, a first-in-class treatment for obstructive HCM, may be capable of achieving a sustained, marked relief in symptoms and defer the need for septal reduction procedures. However, close echocardiographic monitoring is important to reduce the risk of heart failure.

This new drug comment was finalised on 16 December 2024.

At the time this new drug comment was prepared, the Australian Public Assessment Report was available from the Therapeutic Goods Administration. The sponsor did not provide the clinical evaluation report.

 

References

1. Cardiac Society of Australia and New Zealand. Diagnosis and Management of Hypertrophic Cardiomyopathy. 2016. [cited 2024 Dec 12]
2. Therapeutic Goods Administration. Australian Public Assessment Report for Camzyos. Department of Health and Aged Caree; 2023. [cited 2024 Dec 12]
3. Therapeutic Goods Administration. Australian Product Information – Camzyos (mavacamten) capsule blister pack. Department of Health and Aged Care; 2024. [cited 2024 Dec 12]
4. Olivotto I, Oreziak A, Barriales-Villa R, Abraham TP, Masri A, Garcia-Pavia P, et al. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2020;396:759-69.
5. Garcia-Pavia P, Oreziak A, Masri A, Barriales-Villa R, Abraham TP, Owens AT, et al. Long-term effect of mavacamten in obstructive hypertrophic cardiomyopathy. Eur Heart J 2024.
6. Desai MY, Owens A, Geske JB, Wolski K, Naidu SS, Smedira NG, et al. Myosin Inhibition in Patients With Obstructive Hypertrophic Cardiomyopathy Referred for Septal Reduction Therapy. J Am Coll Cardiol 2022;80:95-108.
7. Desai MY, Wolski K, Owens A, Geske JB, Saberi S, Wang A, et al. Mavacamten in Patients With Hypertrophic Cardiomyopathy Referred for Septal Reduction: Week 128 Results from VALOR-HCM. Circulation 2024.

 

The new drug comments in Australian Prescriber are prepared by the editors and reviewed by the Editorial Advisory Committee. Some of the views expressed on newly approved products should be regarded as preliminary, as there may be limited published data at the time of publication, and little experience in Australia of their safety or efficacy. Before new drugs are prescribed, it is important that more detailed information is obtained from the approved product information, a medicines information centre or some other appropriate source.

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