Mavacamten for symptomatic obstructive hypertrophic cardiomyopathy
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Hypertrophic cardiomyopathy is the most common genetic heart disease, with prevalence estimates from one in 200 to one in 500. However, the true prevalence is poorly understood due to likely underdiagnosis.
The diagnostic criteria for hypertrophic cardiomyopathy (HCM) are based on increased septal wall thickness, at least 15 mm in the absence of secondary causes or at least 13 mm in familial HCM. General clinical markers of HCM include left ventricular hypertrophy, myocardial hypercontractility, diastolic dysfunction and hallmark left ventricular outflow tract (LVOT) obstruction (ie, gradient of at least 30 mm Hg). The presence of LVOT obstruction is associated with an increase in morbidity and mortality. The presentation of patients with hypertrophic obstructive cardiomyopathy (HOCM) can range from being asymptomatic to, in 30% to 40% of patients, experiencing HF symptoms with dyspnea or edema, syncope, arrhythmias, and even sudden cardiac death (SCD).
Guideline treatment recommendations for HCM
The 2020 American College of Cardiology/American Heart Association HCM guideline recommendations focus on pharmacologic treatment for symptomatic relief with beta-blockers, non-dihydropyridine calcium channel blockers (non-DHP CCBs), diuretics and disopyramide. Non-vasodilating beta-blockers are first-line agents and non-DHP CCBs are generally second-line. Non-DHP CCBs are limited by vasodilation, which can reduce preload and worsen pulmonary congestion in patients with LVOT obstruction. No evidence is available to clearly support concomitant use of beta-blockers with non-DHP CCBs. Diuretics must be used with caution so as not to deleteriously reduce preload. In patients who remain significantly symptomatic despite optimized medical therapy, disopyramide or invasive septal reduction therapy may be considered. Disopyramide therapy, used for its negative inotropic effects, is limited by anticholinergic side effects and ventricular arrhythmia risk, whereas septal reduction therapy, myectomy or alcohol ablation is invasive and requires referral to a comprehensive HCM center. Finally, implantable cardioverter defibrillators are recommended for patients with major risk factors for SCD, previous cardiac arrest or previous sustained ventricular tachycardia.
Despite current pharmacologic and interventional therapies available in HOCM, an unmet need in therapeutics exists. None of the pharmacologic options currently available specifically target the underlying pathophysiology of the disease, modify its progression or promote disease regression.
A new pharmacotherapy option: Mavacamten
A novel medication, mavacamten (Bristol Myers Squibb), was developed to target the underlying pathophysiology of HCM. As a selective allosteric inhibitor of cardiac myosin ATPase, mavacamten reduces actin-myosin cross-bridge formation and contractility, thus improving myocardial energetics. Previous phase 2 trials have revealed improvements in HCM-related surrogate endpoints. In the 12-week, open-label PIONEER-HCM trial, mavacamten significantly reduced the postexercise LVOT gradient and was well tolerated. In the 16-week, randomized, double-blind, placebo-controlled MAVERICK-HCM trial, mavacamten reduced brain natriuretic peptide and troponin levels, which are important clinical markers of myocardial wall stress and injury and are used to predict prognosis in HCM. These data supported further evaluation of mavacamten on more clinically relevant outcomes.
EXPLORER-HCM was a phase 3, multicenter, randomized, double-blind, placebo-controlled trial that expanded upon PIONEER-HCM and MAVERICK-HCM to assess whether mavacamten would improve functional capacity and symptom burden in patients with relatively advanced HOCM. Patients enrolled had a peak LVOT gradient of at least 50 mm Hg, left ventricular ejection fraction of at least 55% and NYHA class II to III symptoms. Patients with a history of syncope in the last 6 months, QTc of at least 500 milliseconds and atrial fibrillation were excluded. Background pharmacotherapy included beta-blockers or non-DHP CCBs; disopyramide was not permitted. Patients taking CYP2C19 inhibitors, strong CYP3A4 inhibitors or St. John’s wort within 2 weeks were also excluded. Patients with AF were required to be taking anticoagulation and have adequate rate control for 6 months prior to randomization.
The trial randomly assigned 251 patients to therapy with mavacamten or placebo for 30 weeks. The starting dose of mavacamten was 5 mg by mouth daily with dose adjusted to 2.5 mg to 15 mg daily at weeks 8 and 14 based on LVOT gradient on therapy and mavacamten plasma concentrations (target trough concentration of 350-700 ng/mL). The primary analysis was a composite outcome that assessed improvement in functional status using peak oxygen consumption (peak VO2) on cardiopulmonary exercise testing and NYHA class. The primary composite outcome was defined as a 1.5 mL/kg/min or greater increase in peak VO2 and at least one NYHA class reduction, or a 3 mL/kg/min or greater improvement in peak VO2 and no NYHA class worsening.
Overall, 37% of patients receiving mavacamten met the composite functional outcome compared with 17% of patients receiving placebo (difference, 19.4; 95% CI, 8.7-30.1; P = .0005). All secondary outcomes, including HCM subjective well-being as measured by the Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness of Breath subscore (HCMSQ-SoB) and health-related quality of life as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score, significantly favored mavacamten. Exploratory results revealed that 27% of patients assigned mavacamten achieved complete response, defined as all LVOT gradients less than 30 mm Hg and NYHA class I symptoms, compared with 1% of patients assigned placebo (difference, 26.6; 95% CI, 18.3-34.8). The majority of patients continued on treatment for the 30-week trial duration (97%). Most adverse events were mild, and there was a similar rate of serious adverse events between mavacamten and placebo.
Considerations for use
Mavacamten appears to be a safe and practical option for patients with relatively advanced HOCM beyond typical first-line therapies, ie, symptomatic patients with HOCM despite beta-blocker or non-DHP CCB therapy. Outcomes are especially promising in that more than 25% of patients on mavacamten achieved complete response. It is unclear what effects mavacamten would have in disopyramide-treated patients, as they were excluded from EXPLORER-HCM. It is also uncertain if mavacamten use should routinely precede disopyramide in clinical practice, but the positive efficacy and favorable safety data from EXPLORER-HCM supports its preference. Finally, mavacamten may prove especially useful in those patients who are being considered for septal reduction therapy to delay time to intervention supported by efficacy in patients with NYHA class III HOCM symptoms at baseline.
Mavacamten is not yet FDA-approved, but its FDA new drug application has been accepted with approval consideration pending Jan. 28, 2022. If mavacamten receives FDA approval, there are several considerations for clinical use that clinicians should be aware. First, as done in EXPLORER-HCM, mavacamten dosing may require adjustment based on LVOT gradients on therapy and drug levels, with potential interruptions in therapy if there are concerning drops in LVEF or supratherapeutic drug levels (> 1,000 ng/mL). Second, it is unclear what type of safety and efficacy mavacamten may have in patients with baseline LVEF less than 55%, as these patients were excluded from EXPLORER-HCM out of caution for potential drops in LVEF with myosin inhibition. Additional information is required about use with drugs that prolong the QT interval as well as the potential for drug-drug interactions, as patients with a baseline QT of at least 500 milliseconds or on interacting medications were excluded from EXPLORER-HCM. Third, future evaluations will help determine mavacamten’s place in therapy with regard to concomitant disopyramide therapy. Lastly, drug costs associated with this novel therapy may limit its utility, as pricing will ultimately define mavacamten’s economic place in therapy. Information available from the Institution for Clinical and Economic Review (ICER) stated that at an estimated placeholder cost of $75,000 per year, mavacamten would not be cost-effective. However, this is a theoretical projection, as the actual cost-effectiveness of mavacamten will depend on its price, which is yet to be determined.
On the horizon
Mavacamten continues to be studied in HCM. The VALOR-HCM trial will investigate whether mavacamten can provide a noninvasive treatment option for patients with HOCM eligible for septal reduction therapy by assessing whether mavacamten helps reduce the need for septal reduction therapy or delays time to invasive therapy. VALOR-HCM will also include patients on disopyramide and with NYHA class I symptoms. Also upcoming is the MAVA-LTE trial, an extension of EXPLORER-HCM and MAVERICK-HCM, which will investigate the long-term safety of mavacamten for up to 5 years. There are no current evaluations of upstream mavacamten therapy in patients without LVOT obstructions.
In conclusion, with mavacamten likely on the horizon, the path to clinical improvement for patients with HOCM may not be so obstructed in the future.
- References:
- Bristol Myers Squibb. news.bms.com/news/details/2021/U.S.-Food-and-Drug-Administration-FDA-Accepts-Bristol-Myers-Squibbs-Application-for-Mavacamten-in-Symptomatic-Obstructive-Hypertrophic-Cardiomyopathy-oHCM/default.aspx. Published March 19, 2021. Accessed Nov. 11, 2021.
- Clinicaltrials.gov. clinicaltrials.gov/ct2/show/NCT03723655. Accessed Nov. 11, 2021.
- Clinicaltrials.gov. clinicaltrials.gov/ct2/show/NCT04349072. Accessed Nov. 11, 2021.
- Desai MY, et al. Am Heart J. 2021;doi:10.1016/j.ahj.2021.05.007.
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- Institute for Clinical and Economic Review. icer.org/wp-content/uploads/2021/04/ICER_HCM_Revised_Report_100721.pdf. Published Oct. 7, 2021. Accessed Nov. 11, 2021.
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- Olivotto I, et al. Lancet. 2020;doi:10.1016/S0140-6736(20)31792-X.
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- For more information:
- Kiana Green, PharmD, is a PGY2 cardiology pharmacy practice resident at West Palm Beach VA Medical Center in West Palm Beach, Florida. She can be reached at kiana.green@va.gov.
- Augustus (Rob) Hough, PharmD, BCPS, BCCP, is clinical pharmacy specialist in cardiology and the PGY2 Cardiology Pharmacy Residency Director at West Palm Beach VA Medical Center. He can be reached at augustus.hough@va.gov.
- Sarah A. Spinler, PharmD, FCCP, FAHA, FASHP, AACC, BCPS (AQ Cardiology), is the Cardiology Today Pharmacology Consult column editor. She is professor and chair of the department of pharmacy practice in the School of Pharmacy and Pharmaceutical Sciences at Binghamton University. She can be reached at sspinler@binghamton.edu.
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