Myqorzo Drug Information

MYQORZO is indicated for the treatment of adults with symptomatic obstructive hypertrophic cardiomyopathy (oHCM) to improve functional capacity and symptoms.

Evaluation Before and During Use of MYQORZO Initiation or up-titration of MYQORZO in patients with LVEF <55% is not recommended. Patients may develop heart failure while taking MYQORZO. Regular LVEF and Valsalva left ventricular outflow tract gradient (LVOT-G) assessment is needed for titration to achieve an appropriate target Valsalva LVOT-G, while maintaining LVEF ≥50% and avoiding heart failure symptoms.

Recommended Dosage and Administration

The recommended starting dose of MYQORZO is 5 mg orally once daily. The maintenance dose of MYQORZO is individualized based on the patient's LVEF and LVOT-G. Recommendations for dosing based on LVEF and LVOT-G criteria are provided in Table 1.

Table 1: Perform an echocardiographic assessment 2 to 8 weeks after initiation of treatment or any dose adjustment (e.g., due to LVEF and LVOT-G criteria or drug interaction). Consider monitoring LVEF and adjust the dose per Table 1 as needed, in patients with an intercurrent illness (e.g., severe infection or COVID-19), new arrhythmia (e.g., new or uncontrolled atrial fibrillation or other uncontrolled tachyarrhythmia) or any other conditions that may impair systolic function. Do not increase the dose until the intercurrent illness or new arrhythmia has resolved or stabilized.

MYQORZO should be taken once daily with or without meals at about the same time every day. Swallow tablets whole.

Dosage Modifications for Drug Interactions Initiate MYQORZO at the recommended starting dose of 5 mg once daily in patients who are on stable therapy with fluconazole, voriconazole, fluvoxamine, strong CYP2C9 inhibitors, or in patients discontinuing a moderate to strong CYP3A inducer. Concomitant Administration with Fluconazole or Voriconazole In patients who initiate fluconazole (if used for more than 3 days) or voriconazole, reduce the dose of MYQORZO to 5 mg if they are currently receiving 15 mg or 20 mg. Avoid concomitant use if patients are currently receiving MYQORZO 5 mg or 10 mg.

Assess LVEF and LVOT-G 2 to 8 weeks after initiation of fluconazole or voriconazole and titrate the dose of MYQORZO according to Table 1.

Missed Dose If a dose is missed, it should be taken as soon as possible on the same day. The next scheduled dose should be taken at the usual time the following day. Two doses of MYQORZO should not be taken on the same day.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of MYQORZO was evaluated in SEQUOIA-HCM, a phase 3, randomized, double-blind, placebo-controlled study. The median treatment duration for patients receiving MYQORZO was ~24 weeks (range 4 to 29 weeks).

Hypertension (8% vs. 2%) was the only adverse reaction occurring in >5% of patients and more commonly on MYQORZO than on placebo. Eligible oHCM patients were able to participate in an ongoing, open-label, single-arm, long-term safety study (FOREST-HCM). Based on available data, the safety profile of MYQORZO in FOREST-HCM was similar to that observed in SEQUOIA-HCM.

Effects on Systolic Function In SEQUOIA-HCM, the mean (SD) resting LVEF at baseline was 75% in both treatment groups. Consistent with the mechanism of action of MYQORZO, LS mean (SE) change from baseline in LVEF was -7% in the MYQORZO group and -2% in the placebo group at the end of the 24-week treatment period. Four weeks after the end of treatment, mean LVEF was similar between the MYQORZO and placebo groups.

Reductions in LVEF to <50% did not require treatment interruption and were not associated with clinical heart failure. Effects on Blood Pressure In SEQUOIA-HCM, the mean (SD) systolic/diastolic blood pressure (SBP/DBP) at baseline was 125/75 mmHg for patients in the MYQORZO group and 126/74 mmHg in the placebo group. There was a greater mean change from baseline in SBP/DBP (SD) in the MYQORZO group compared to the placebo group at the end of the 24-week treatment period.

In SEQUOIA-HCM, SBP ≥160 mmHg was observed in approximately 16% of patients in the MYQORZO group and 8% of patients in the placebo group. MYQORZO-associated increases in blood pressure are consistent with relief of LVOT obstruction and improved cardiac output.

Drugs that inhibit multiple pathways of MYQORZO elimination, strong CYP2C9 inhibitors, or moderate-to-strong CYP3A inducers may increase risk of heart failure. MYQORZO dose reduction and additional monitoring may be required when initiating or discontinuing these drugs. 7.1. Potential for Other Drugs to Affect Plasma Concentrations of MYQORZO Aficamten is primarily metabolized by CYP2C9 and, to a lesser extent by CYP3A, CYP2D6, and CYP2C19.

Concomitant administration of drugs that inhibit multiple P450 pathways of aficamten elimination, strong inhibitors of CYP2C9, and moderate-to-strong inducers of CYP3A, may affect the exposure of aficamten (see Table 2 ). Table 2: Established and Potentially Significant Pharmacokinetic Drug-Drug Interactions with MYQORZO Initiate MYQORZO at 5 mg in patients on stable therapy with fluvoxamine. Fluconazole or Voriconazole Clinical Impact Fluconazole is a moderate CYP2C9 inhibitor, moderate CYP3A inhibitor, and strong CYP2C19 inhibitor.

Coadministration with fluconazole is observed, and voriconazole is predicted, to increase aficamten exposure, which may increase the risk of developing heart failure due to systolic dysfunction. Prevention or Management Initiate MYQORZO at 5 mg in patients on stable therapy with fluconazole or voriconazole. Avoid concomitant use if currently receiving MYQORZO 5 mg or 10 mg.

Strong CYP2C9 inhibitors Clinical Impact Coadministration with a strong CYP2C9 inhibitor is predicted to increase the exposure of aficamten, which may increase the risk of developing heart failure due to systolic dysfunction. Prevention or Management Initiate MYQORZO at 5 mg in patients who are on stable therapy with a strong CYP2C9 inhibitor. CYP Inducers Rifampin Clinical Impact Rifampin is a strong CYP3A inducer, strong CYP2C19 inducer, and moderate CYP2C9 inducer.

Coadministration of rifampin decreases aficamten exposure, which may reduce the effectiveness of MYQORZO. Prevention of Management Concomitant use with rifampin is contraindicated. Other moderate-to-strong CYP3A inducers Clinical Impact Concomitant use with a moderate to strong CYP3A inducer decreases aficamten exposure, which may reduce MYQORZO effectiveness.

Pregnancy Risk Summary There are no available data on the use of MYQORZO during pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. The underlying maternal condition during pregnancy poses a risk to the mother and fetus (see Clinical Considerations ). In embryo-fetal and pre- and postnatal development studies, when pregnant rats were administered aficamten during the period of organogenesis, aficamten increased the incidence of structural malformations at exposures ≥4-times the maximum recommended human dose (MRHD) of 20 mg based on free area under the concentration curve (AUC).

No adverse effects on development were seen at 3-times the MRHD exposure (see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, and other adverse outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. There is a pregnancy safety study for MYQORZO. If MYQORZO is administered during pregnancy, or if a patient becomes pregnant while receiving MYQORZO or within 3 weeks after the last dose of MYQORZO, healthcare providers should report MYQORZO exposure by contacting Cytokinetics, Inc. at 1-833-633-2986.

Clinical Considerations Disease-Associated Maternal and Embryo-Fetal Risk Obstructive HCM in pregnancy has been associated with increased risk for preterm birth. Data Animal Data Aficamten given to pregnant rats (2, 6 and 9 mg/kg/day) during the period of organogenesis was associated with increased external fetal malformations (kinked tail) at aficamten exposures 5-times the clinical exposures at the MRHD based on free AUC, with uncertain human relevance. Increased post-implantation loss (early and late resorptions) and decreased mean fetal body weight occurred in the presence of significant maternal toxicity at exposures 5-times the clinical exposures at the MRHD.

No adverse effects on embryofetal development were observed at 6 mg/kg/day, representing 3-times the clinical exposure at the MRHD. However, no increase in malformations was observed at the high dose of 20/15 mg/kg/day, a dose that caused significant maternal toxicity (leading to dose reduction from 20 to 15 mg/kg/day during the study) at clinically relevant exposures. Pregnant rats given aficamten (0.5, 1.5, 6 mg/kg/day) during embryofetal organogenesis through offspring weaning in a pre- and postnatal development study had reduced offspring viability at the 6 mg/kg/day in the presence of maternal toxicity, at 4-times the clinical exposure at the MRHD based on free AUC.

An increased number of offspring with bent tails was also observed at the 6 mg/kg/day. No adverse maternal toxicity or developmental effects occurred at 1.5 mg/kg/day, which corresponds to clinical exposure at the MRHD. Aficamten did not affect neurobehavioral parameters, sexual maturation, or reproductive function of the offspring at any dose.

Pediatric Use The safety and effectiveness of MYQORZO in pediatric patients have not been established.

MYQORZO is contraindicated with concomitant use of rifampin. Rifampin

Clinical Experience and Effects There have been no reports of overdose with MYQORZO. Cardiovascular effects of overdose may include reduced LVEF, heart failure, and hypotension. Signs and symptoms of heart failure such as dyspnea, fatigue, leg edema, or elevations in NT-proBNP should prompt an evaluation of cardiac function.

Management Discontinue MYQORZO treatment. Provide medically supportive measures to maintain hemodynamic stability and monitor left ventricular function. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.