Optimizing mavacamten for treatment of obstructive hypertrophic cardiomyopathy
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Key takeaways:
- Mavacamten presents dosing and drug-drug interaction challenges.
- A multidisciplinary approach featuring a clinical pharmacist can optimize mavacamten therapy for patients with obstructive HCM.
The introduction of mavacamten represents a major shift in the treatment of obstructive hypertrophic cardiomyopathy, but raises dosing and drug-drug interaction challenges.
For these reasons, the FDA has mandated that a Risk Evaluation and Mitigation Strategies (REMS) program be undertaken by any institution that prescribes mavacamten (Camzyos, Bristol Myers Squibb). This article will show how a multidisciplinary approach featuring a clinical pharmacist specializing in cardiology can optimize therapy and monitoring for patients with obstructive HCM who need mavacamten.
The landscape of HCM
HCM is generally defined by left ventricular hypertrophy, with a maximal end-diastolic wall thickness of at least 15 mm anywhere in the left ventricle, in a patient without another cardiac, systemic or metabolic disease leading to changes in sarcomeres.
The degree of LV outflow tract obstruction (LVOTO), originating from a combination of septal hypertrophy and anatomic changes to the mitral valve, largely dictates symptoms and therapy for HCM; an LV outflow tract (LVOT) gradient of at least 30 mm Hg is indicative of obstruction. Patients with HCM may not develop significant LVOTO or experience activity-limiting symptoms; treatment for these patients focuses on management of arrhythmias such as atrial fibrillation, reduction of LV filling pressures and relieving angina.
Patients with HCM and LVOTO should remain well hydrated, limit alcohol consumption, avoid vasodilating medications and attempt weight loss if appropriate. AF may worsen symptoms; attempts to restore normal sinus rhythm or improve rate control should be made. Risk for sudden cardiac death should be assessed and, when appropriate, a primary prevention defibrillator should be offered.
Goals of treatment for symptomatic HCM with LVOTO and elevated LVOT gradients are to decrease the LVOT gradients, lower the patient’s NYHA functional class and improve symptoms. Medications traditionally indicated to decrease LVOT gradients include nonvasodilating beta-blockers, nondihydropyridine calcium channel blockers and the antiarrhythmic disopyramide. Unfortunately, none of these medications target the mechanism of HCM, and tolerability often limits dose titration. Patients with LVOT gradients greater than 50 mm Hg who are intolerant of, or refractory to, these traditional pharmacologic therapies may require septal reduction therapy such as alcohol septal ablation or septal myectomy.
Mavacamten
Mavacamten, a reversible and selective inhibitor of cardiac myosin, is indicated for the treatment of adults with symptomatic NYHA class II/III obstructive HCM to improve functional capacity and symptoms.
Mavacamten decreases the amount of excess myosin-actin cross-bridging of the cardiac sarcomere present in HCM, resulting in less contractility, decreased dynamic LVOTO and improved cardiac filling pressures.
The Table summarizes the study design and findings from three major randomized controlled clinical trials of mavacamten to date. Additional discussion on the outcomes is below.
EXPLORER-HCM trial
The EXPLORER-HCM trial randomly assigned 251 patients to treatment with mavacamten or placebo. Among the cohort, 73% of patients had NYHA class II symptoms and 92% were on baseline therapy with a beta-blocker or calcium channel blocker.
The primary endpoint, a composite of at least 1.5 mL/kg/min increase in peak oxygen consumption (peak VO2) and at least one NYHA class reduction or an at least 3 mL/kg/min improvement in peak VO2 and no worsening of NYHA class, occurred more frequently in the mavacamten group (Table). All secondary endpoints were also in favor of mavacamten, including reduction in LVOT gradient, increase in peak VO2, improved NYHA class and patient-reported symptoms.
Adverse effects were generally mild, with syncope and dizziness occurring more often in the mavacamten group. Nine patients (seven mavacamten, two placebo) had an LVEF drop to less than 50%, all of which normalized after stopping treatment.
VALOR-HCM trial
For the VALOR-HCM trial, 108 patients qualified for the week 56 evaluation. In the mavacamten group, 92.7% of patients improved by at least one NYHA class and 43.6% of patients improved by at least two NYHA classes. In the placebo crossover group, 72.5% of patients improved by at least one NYHA class and 35.3% of patients improved by at least two NYHA classes. Six patients (5.5%) from both groups chose to undergo septal reduction therapy. The occurrence rate of developing a LVEF less than 50% was similar between the two groups.
MAVA-LTE: EXPLORER-LTE cohort
MAVA-LTE is an ongoing trial looking at long-term mavacamten use (> 5 years) for obstructive HCM. Patients who completed 38 weeks in the EXPLORER-HCM trial were eligible for enrollment in MAVA-LTE. Interim analysis suggests long-term use outcomes are similar to those shown in EXPLORER-HCM and VALOR-HCM. The mean change in LVOT gradient was –35.6 mm Hg at 48 weeks and–32.8 mm Hg at 84 weeks. Mean LVEF was similar at week 48 through week 84. At week 48, 67.5% of patients had improved by at least one NYHA class. Treatment-emergent adverse effects were mostly mild or moderate in severity, with the most frequent being fatigue (10.4%), dizziness (10%), hypertension (10%) and AF (9.1%). Of the 21 patients who experienced AF, 11 patients had new-onset AF. At the time of data collection, 16 of the 21 patients had resolution of their AF.
Mitigating risks of mavacamten
Mavacamten decreases LVOT gradients and improves patient symptoms by directly decreasing cardiac contractility. By this same mechanism, patients can develop decreased LV systolic function leading to HF exacerbations. An FDA-mandated REMS program focusing on potential drug interactions and LVEF monitoring was created to mitigate this risk.
Potential Drug-Drug Interactions
Mavacamten is hepatically metabolized, mostly by CYP2C19, and, to a lesser extent, CYP3A4 and CYP2C9. Its use is contraindicated with moderate to strong CYP2C19 inhibitors, strong CYP3A4 inhibitors, moderate to strong CYP2C19 inducers or strong CYP3A4 inducers. Dose reductions for mavacamten are required when combined with a weak CYP2C19 inhibitor or moderate CYP3A4 inhibitor. Currently, the approved dosing strategy for mavacamten in the U.S. does not mandate CYP2C19 genotyping prior to initiation. However, the dosing strategy is focused on monitoring for and identifying toxicities early. In other countries, product labeling recommends CYP2C19 genotyping with a reduced initial dose for poor metabolizers.
Dosing b ased on LVEF and LVOT g radient
The mavacamten dosing algorithm is based on assessment of LVEF and LVOT gradients via echocardiogram at baseline, 4 weeks, 8 weeks and 12 weeks of therapy. The initial 12 weeks of oral therapy at 5 mg daily focuses on safety, and the dose of mavacamten may not be increased even if the LVOT gradients remain elevated. If there are no significant reductions in LVEF after the first 12 weeks of therapy and the peak LVOT gradient remains at least 30 mm Hg, the dose may be increased. The maintenance echocardiogram frequency is determined by LVEF and the need for dose decrease or interruption, in addition to LVOT gradient and indication to uptitrate the mavacamten dose; the maximum recommended dose is 15 mg once daily.
Multidisciplinary approach to mavacamten therapy
At Geisinger, an integrated delivery network, we have successfully implemented a multidisciplinary team approach to the initiation, dispensing and management of mavacamten therapy (Figure). During initiation, a clinical pharmacist specializing in cardiology embedded within a Geisinger Cardiology HCM clinic, and enrolled as a REMS provider designee, facilitates the necessary steps for REMS enrollment, completes a comprehensive medication reconciliation to screen for drug-drug interactions, and counsels on safe medication use. The cardiology clinical pharmacist coordinates prior authorization and patient cost assistance via pharmacy department support teams. A collaborative practice agreement with the REMS certified physician allows the pharmacist to prescribe mavacamten to Geisinger’s REMS-certified specialty pharmacy for dispensing.
Geisinger specialty pharmacy pharmacists assist with the ongoing assessment for side effects and screen for drug-drug interactions at the time of each mavacamten dispensing. Direct and timely communication between the Geisinger specialty pharmacy and the HCM clinic prevents delays in dispensing, avoids interruptions in therapy, facilitates faster access during dose adjustments and notifies the clinic with therapy adherence concerns.
Follow-up with the patient after initiating mavacamten therapy is completed with the cardiology clinical pharmacist to assess for tolerance, adjust other medications as indicated and coordinate the ordering and scheduling of appropriately timed echocardiograms to meet REMS submission requirements. Echocardiogram results are reviewed by the REMS certified physician and pharmacist prior to patient follow-up, REMS status form submission, ongoing mavacamten dispensing at the Geisinger specialty pharmacy and scheduling of future echocardiograms. Patients continue to have periodic in-person follow up with the REMS-certified physician in the HCM clinic throughout mavacamten treatment.
The Figure summarizes the multidisciplinary clinic structure and workflow through the integrated delivery network.
Optimal therapy and monitoring
Mavacamten has been shown to be effective and well tolerated for the treatment of obstructive HCM. Due to the potential for drug-drug interactions and decreases in LV systolic function leading to HF exacerbations, mavacamten must be prescribed under the guidance of a REMS program. Clinical pharmacist integration into an interdisciplinary HCM clinic team promotes appropriate medication therapy and monitoring for HCM clinic patients receiving mavacamten.
References:
- Arbelo E, et al. Eur Heart J. 2023;doi:10.1093/eurheartj/ehad194.
- Camzyos [package insert]. Princeton, NJ: Bristol-Myers Squibb Co.; 2024. https://packageinserts.bms.com/pi/pi_camzyos.pdf. Revised April 2024. Accessed Aug. 8, 2024.
- Desai MY, et al. JAMA Cardiol. 2023;doi:10.1001/jamacardio.2023.3342.
- McGurk KA, et al. Circulation. 2024;doi:10.1161/CIRCULATIONAHA.123.066916.
- Olivotto I, et al. Lancet. 2020;doi:10.1016/S0140-6736(20)31792-X.
- Ommen SR, et al. Circulation. 2020;doi:10.1161/CIR.0000000000000937.
- Rader F, et al. JACC Heart Fail. 2024;doi:10.1016.j.jchf.2023.09.028.
For more information:
Sarah Knauer, PharmD, BCPS, is a clinical pharmacist in the Geisinger Enterprise Pharmacy department specializing in cardiology with a clinical practice site at the Geisinger Heart and Vascular Institute at Geisinger Wyoming Valley Medical Center in Wilkes Barre, Pennsylvania. Knauer can be reached at sknauer@geisinger.edu.
Nathan Sauers, PharmD, is a clinical pharmacist in the Geisinger Enterprise Pharmacy department specializing in cardiology with a clinical practice site at the Geisinger Heart and Vascular Institute at Geisinger Medical Center in Danville, Pennsylvania. Sauers can be reached at nsauers@geisinger.edu.
Sarah A. Spinler, PharmD, FCCP, FAHA, FASHP, AACC, BCPS (AQ Cardiology), is the Healio | Cardiology Today Pharmacology Consult column editor. Spinler is professor and chair of the department of pharmacy services in the School of Pharmacy and Pharmaceutical Sciences at Binghamton University. Spinler can be reached at sspinler@binghamton.edu.
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