MYQORZO

1 INDICATIONS AND USAGE MYQORZO is indicated for the treatment of adults with symptomatic obstructive hypertrophic cardiomyopathy (oHCM) to improve functional capacity and symptoms. MYQORZO is a cardiac myosin inhibitor indicated for the treatment of adults with symptomatic obstructive hypertrophic cardiomyopathy (oHCM) to improve functional capacity and symptoms. ( 1 )

2 DOSAGE AND ADMINISTRATION Recommended starting dose is 5 mg orally once daily. ( 2.1 ) Dosage is individualized based on echocardiographic assessments and clinical status. Refer to Full Prescribing Information for instructions on dosage modification. ( 2.1 , 2.2 ) 2.1 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. 2.2 Recommended Dosage and Administration The recommended starting dose of MYQORZO is 5 mg orally once daily. Increase the dose every 2 to 8 weeks by 5 mg until a maintenance dose or the maximum recommended dose of 20 mg once daily is achieved. 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: Dose Adjustment of MYQORZO LVEF Valsalva LVOT-G Dose Adjustment ≥55% ≥30 mmHg Increase dose by 5 mg (up to the maximum dose of 20 mg once daily) ≥55% <30 mmHg Maintain Dose <55% and ≥50% Any Maintain Dose <50% and ≥40% Any Decrease dose by 5 mg Decrease dose as follows: 20 mg to 15 mg; 15 mg to 10 mg; 10 mg to 5 mg If already on 5 mg, interrupt treatment for at least 7 days <40% Any Interrupt treatment for at least 7 days 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). After a treatment interruption due to low LVEF, resume treatment, no earlier than 7 days, when LVEF ≥55% and re-initiate dose titration at the starting dose of 5 mg (see Table 1 ). After the maintenance dose has been established, assess LVEF and Valsalva LVOT-G every 6 months, or every 3 months in patients with LVEF <55% to ≥50%. 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. 2.3 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 [see Dosage and Administration (2.2) , Warnings and Precautions (5.3) and Drug Interactions (7.1) ] . Concomitant Administration with Fluvoxamine or Strong CYP2C9 Inhibitors In patients who initiate fluvoxamine or a strong CYP2C9 inhibitor, reduce the dose of MYQORZO (20 mg to 10 mg; 15 mg to 5 mg; 10 mg to 5 mg). For patients currently receiving MYQORZO 5 mg, maintain the 5 mg dose. Assess LVEF and LVOT-G 2 to 8 weeks after inhibitor initiation and titrate the dose of MYQORZO according to Table 1 [see Dosage and Administration (2.2) , Warnings and Precautions (5.3) and Drug Interactions (7.1) ] . Concomitant Administration with Moderate to Strong CYP3A Inducers In patients who are on stable the …

3 DOSAGE FORMS AND STRENGTHS MYQORZO is available as tablets in the following strengths: Tablets: 5 mg - purple, round tablet debossed with "5" on one side and "CK" on the other side. Tablets: 10 mg - purple, triangular tablet debossed with "10" on one side and "CK" on the other side. Tablets: 15 mg - purple, pentagonal tablet debossed with "15" on one side and "CK" on the other side. Tablets: 20 mg - purple, oval tablet debossed with "20" on one side and "CK" on the other side. Film-coated tablets: 5 mg, 10 mg, 15 mg, 20 mg. ( 3 )

4 CONTRAINDICATIONS MYQORZO is contraindicated with concomitant use of rifampin [see Warnings and Precautions (5.3) and Drug Interactions (7.1) ] . Rifampin ( 4 )

6 ADVERSE REACTIONS The following adverse reaction is discussed in other sections of labeling: Heart Failure [see Warnings and Precautions (5.1) ] The most common adverse reaction was hypertension (8%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Cytokinetics at 1-833-633-2986 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 [see Clinical Studies (14) ] . Of the 282 adults with oHCM, 142 patients received daily doses of MYQORZO (initiated at 5 mg and titrated up to a maximum dose of 20 mg) and 140 patients received placebo. 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% (6) in both treatment groups. Consistent with the mechanism of action of MYQORZO, LS mean (SE) change from baseline in LVEF was -7% (0.6) in the MYQORZO group and -2% (0.6) 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. During the 24-week treatment period, 5 (4%) patients in the MYQORZO group and 1 (1%) patient in the placebo group experienced a reversible reduction in LVEF to <50% (median LVEF: 47%; range 34% - 49% for these 5 patients in the MYQORZO group). Reductions in LVEF to <50% did not require treatment interruption and were not associated with clinical heart failure [see Warnings and Precautions (5.1) ] . Effects on Blood Pressure In SEQUOIA-HCM, the mean (SD) systolic/diastolic blood pressure (SBP/DBP) at baseline was 125(16)/75(11) mmHg for patients in the MYQORZO group and 126(16)/74(11) 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 [2(13)/3(8) mmHg and -3(14)/-1(9) mmHg, respectively]. Four weeks after the end of treatment, the mean SBP/DBP was similar between the MYQORZO and placebo groups. 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.

7 DRUG INTERACTIONS 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. ( 2.3 , 7.1 ) 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 Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ] (see Table 2 ). Table 2: Established and Potentially Significant Pharmacokinetic Drug-Drug Interactions with MYQORZO Inhibitors of Multiple CYPs Fluvoxamine Clinical Impact Fluvoxamine is a strong CYP2C19 inhibitor, weak to moderate CYP3A inhibitor, weak CYP2C9 inhibitor, and weak CYP2D6 inhibitor. Coadministration of fluvoxamine 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 fluvoxamine. In patients who are on MYQORZO treatment and intend to initiate fluvoxamine: Reduce dose of MYQORZO (i.e., 20 mg to 10 mg, 15 mg to 5 mg, or 10 mg to 5 mg) or continue 5 mg [see Dosage and Administration (2.3) ] . Fluconazole or Voriconazole Clinical Impact Fluconazole is a moderate CYP2C9 inhibitor, moderate CYP3A inhibitor, and strong CYP2C19 inhibitor. Voriconazole is a strong CYP3A inhibitor, moderate CYP2C19 inhibitor, and weak CYP2C9 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 [see Clinical Pharmacology (12.3) ] . Prevention or Management Initiate MYQORZO at 5 mg in patients on stable therapy with fluconazole or voriconazole. In patients currently receiving MYQORZO who intend to initiate fluconazole (if used more than 3 days) or voriconazole: Reduce dose of MYQORZO to 5 mg if they are currently receiving MYQORZO 15 mg or 20 mg. Avoid concomitant use if currently receiving MYQORZO 5 mg or 10 mg [see Dosage and Administration (2.3) ] . 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 [see Clinical Pharmacology (12.3) ] . Prevention or Management Initiate MYQORZO at 5 mg in patients who are on stable therapy with a strong CYP2C9 inhibitor. In patients who are on MYQORZO treatment and intend to initiate a strong CYP2C9 inhibitor: Reduce dose of MYQORZO (i.e., 20 mg to 10 mg, 15 mg to 5 mg, or 10 mg to 5 mg) or continue 5 mg [see Dosage and administration (2.3) ]. 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 [see Contraindications (4) and Clinical Pharmacology (12.3) ]. 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 [see Clinical Pharmacology (12.3) ] . The risk of heart failure due to systolic dysfunction may increase with discontinuation of these inducers. Prevention or Management In patients who intend to discontinue a moderate to strong CYP3A Inducer: Reduce dose of MYQORZO (20 mg to 10 mg; 15 mg to 5 mg; 10 mg to 5 mg) or continue 5 mg [see Dosage and Administration (2.3) ].

8 USE IN SPECIFIC POPULATIONS 8.1 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 2% to 4% and 15% to 20%, 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. Pregnant rabbits given aficamten (5, 10 and 20/15 mg/kg/day) during the period of embryofetal organogenesis showed a numerical increase in post-implantation loss (late resorptions) and fetuses with cardiac malformations at 10 mg/kg/day. 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. 8.2 Lactation Risk Summary There are no data on the presence of aficamten in human milk, the effects on the breastfed infant, or the effects on milk production. Aficamten was detected in the plasma of rat pups when dams were dosed with the drug orally during the lactation period . When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for MYQORZO and any potential adverse effects on the breastfed infant from MYQORZO or from the underlying m …

12.1 Mechanism of Action Aficamten is an allosteric and reversible inhibitor of cardiac myosin motor activity. Aficamten reduces the force generated by myosin at the cardiac sarcomere, which contributes to the pathophysiology of HCM. In patients with HCM, myosin inhibition with aficamten reduces cardiac contractility and left ventricular outflow tract (LVOT) obstruction.

11 DESCRIPTION MYQORZO tablets for oral use contain aficamten, a cardiac myosin inhibitor. The chemical name of aficamten is (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1 H -inden-1-yl)-1-methyl-1 H -pyrazole-4-carboxamide. The molecular formula is C 18 H 19 N 5 O 2 and the molecular weight is 337.38 g/mol. The structural formula of aficamten is: Aficamten is a white to off-white to yellow to grey solid that is practically insoluble in water and aqueous buffers (pH 2 – 9), sparingly soluble in acetone and ethanol, and soluble in N-methylpyrrolidone (NMP). MYQORZO is supplied as tablets containing 5 mg, 10 mg, 15 mg, or 20 mg of aficamten per tablet as the active ingredient and the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate (non-bovine), mannitol, microcrystalline cellulose, and sodium lauryl sulfate. The tablet coating contains carmine, FD&C Blue No. 2, glyceryl mono and dicaprylate, polyvinyl alcohol, polyvinyl alcohol graft polyethylene copolymer, talc and titanium dioxide. Chemical Structure

10 OVERDOSAGE 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 [see Warnings and Precautions (5.1) ]. 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.

16 HOW SUPPLIED/STORAGE AND HANDLING MYQORZO is supplied as purple, film-coated tablets containing 5 mg, 10 mg, 15 mg, or 20 mg aficamten. The tablets are debossed on one side with "CK" and the other side with "5", "10", "15" and "20" for the 5, 10, 15, and 20 mg strength, respectively. Tablets are supplied in bottles with child-resistant closure as follows: 5 mg round tablets Bottles of 30 tablets NDC: 82112-105-30 10 mg triangular tablets Bottles of 30 tablets NDC: 82112-110-30 15 mg pentagonal tablets Bottles of 30 tablets NDC: 82112-115-30 20 mg oval tablets Bottles of 30 tablets NDC: 82112-120-30 Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP controlled Room Temperature].