MYQORZO 20 mg film-coated tablets

MYQORZO is indicated for the treatment of symptomatic (New York Heart Association, NYHA, class II-III) obstructive hypertrophic cardiomyopathy (oHCM) in adult patients (see section 5.1).

Treatment should be initiated under the supervision of a physician experienced in the management of patients with cardiomyopathy.

Before treatment initiation, left ventricular ejection fraction (LVEF) should be assessed by echocardiography (see section 4.4). Initiation or up-titration of MYQORZO in patients with LVEF < 55% is not recommended. Regular LVEF and Valsalva left ventricular outflow tract gradient (LVOT‑G) assessment should be performed during titration to achieve an appropriate target Valsalva LVOT‑G, while maintaining LVEF ≥ 50%.

Posology

The dose range is 5 mg to 20 mg (either 5 mg, 10 mg, 15 mg, or 20 mg). The recommended starting dose is 5 mg orally once daily. A starting dose of 10 mg should be considered for patients with LVOT‑G ≥ 100 mmHg. The dose should be increased every 2 to 8 weeks by 5 mg until a maintenance dose or the maximum dose of 20 mg is achieved. The maintenance dose is individualised based on the patient's LVEF and LVOT‑G. Recommendations for dosing based on LVEF and LVOT‑G criteria are in Table 1.

Table 1: Dose adjustment of aficamten

An echocardiographic assessment should be performed 2 to 8 weeks after initiation of treatment, any dose adjustment, or treatment interruption. After a treatment interruption when LVEF < 40%, treatment should be resumed with a dose reduced by 5 mg when LVEF ≥ 55%. If at 5 mg and LVEF < 50%, treatment should be interrupted for 7 days, and treatment can be resumed at 5 mg when LVEF ≥ 55% (see Table 1).

After the maintenance dose has been established, LVEF and Valsalva LVOT‑G should be assessed every 6 months, or every 3 months in patients with LVEF ≥ 50% to < 55%. Consider monitoring LVEF and adjust dose per Table 1, as needed, in patients with 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. Dose increases are not recommended until intercurrent illness or new arrythmia has resolved or stabilised.

Discontinuation of aficamten may result in recurrence of HCM symptoms. Gradual dose reduction may attenuate the rate of symptom recurrence following treatment discontinuation (see section 4.4).

Dose modification with concomitant medicinal products

Concomitant use with moderate CYP2C9 inhibitors that are also moderate-to-strong inhibitors of CYP2D6 or CYP3A e.g. more than a single dose of fluconazole or strong inducers e.g. rifampicin is contraindicated (see section 4.3).

Concomitant use of aficamten with strong CYP2C9 inhibitors should be avoided. If coadministration cannot be avoided, the dose of aficamten should be reduced to 5 mg and LVEF and LVOT‑G assessed every 4 to 8 weeks until a new maintenance dose of aficamten in presence of the inhibitor has been reached (see section 4.5).

The recommended starting dose is 5 mg once daily in patients who are on stable therapy with a weak CYP2C9 inhibitor that is also a moderate-to-strong CYP2D6 or CYP3A inhibitor (e.g. voriconazole, fluvoxamine). The maintenance dose of aficamten should not exceed 15 mg.

For patients who initiate a weak CYP2C9 inhibitor that is also a moderate-to-strong CYP2D6 or CYP3A inhibitor, the dose of MYQORZO should be reduced to 5 mg if they are currently receiving 15 mg or 20 mg. Concomitant use should be avoided if patients are currently receiving MYQORZO 5 mg or 10 mg. The maintenance dose of aficamten should not exceed 15 mg. LVEF and LVOT‑G should be assessed every 4 to 8 weeks until a new maintenance dose of aficamten in presence of the inhibitor has been reached (see section 4.5).

For patients who intend to discontinue a moderate-to-strong CYP2C9 or CYP3A inducer (e.g. carbamazepine), the dose should be reduced (from 20 mg to 10 mg; from 15 mg to 5 mg; from 10 mg to 5 mg) according to Table 2 (see also section 4.5). For patients currently receiving 5 mg, maintain the 5 mg dose. LVEF and LVOT‑G should be assessed after inducer discontinuation. Assessment of LVEF and LVOT‑G and dose titration according to Table 1 is recommended.

Table 2: Dose modification of aficamten with concomitant medicinal products

Missed doses

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 should not be taken the same day.

Elderly

No dose adjustment is required for patients aged 65 years and older (see section 5.2).

Renal impairment

No dose adjustment to the standard recommended dose and titration schedule is required for patients with mild (estimated glomerular filtration rate [eGFR] 60 to 89 mL/min) to moderate (eGFR 30 to 59 mL/min) renal impairment. No dose recommendation can be made for patients with severe (eGFR < 30 mL/min) renal impairment because aficamten has not been studied in patients with severe renal impairment (see section 5.2).

Hepatic impairment

No dose adjustment to the standard recommended dose and titration schedule is required for patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment. No dose recommendation can be made for patients with severe hepatic impairment (Child-Pugh class C) because aficamten has not been studied in patients with severe hepatic impairment (see section 5.2).

Paediatric population

The safety and efficacy of aficamten in children and adolescents below 18 years have not been established. No data are available.

Method of administration

For oral use.

Treatment should be taken once daily with or without meals. The tablet should be swallowed whole with water and not split, crushed, or chewed as these methods have not been studied.

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

• Moderate CYP2C9 inhibitors that are also moderate-to-strong inhibitors of CYP2D6 or CYP3A: e.g. adagrasib and more than a single dose of fluconazole (see section 4.5).

• Strong CYP3A4 inducers that are also moderate CYP2C9 inducers: rifampicin and St. John's wort (see section 4.5).

Systolic dysfunction defined as LVEF < 50%

Aficamten reduces cardiac contractility and LVEF. Heart failure due to systolic dysfunction can occur in patients receiving cardiac myosin inhibitors (see section 4.8).

Patients who experience a severe intercurrent illness (e.g. serious infection) or arrhythmia (e.g. new or uncontrolled atrial fibrillation) may be at greater risk of developing systolic dysfunction and heart failure. Additional monitoring should be considered for asymptomatic LVEF reduction with intercurrent illnesses, and arrhythmias (see section 4.2).

The patient's clinical status and LVEF should be assessed prior to and regularly during treatment and the dose should be adjusted accordingly. New or worsening arrhythmia, dyspnoea, chest pain, fatigue, leg oedema, or elevations in N-terminal pro-B-type natriuretic peptide (NT-proBNP) may be signs and symptoms of heart failure and should also prompt an evaluation of cardiac function.

Heart failure or loss of response to aficamten due to interactions

Aficamten is metabolised by CYP2C9, CYP2D6 and CYP3A enzymes. Initiation of certain medicinal products that inhibit multiple P450 pathways of aficamten elimination (e.g. fluconazole, voriconazole, fluvoxamine), and strong CYP2C9 inhibitors may lead to increased blood concentrations of aficamten, and increase the risk of heart failure due to systolic dysfunction (see sections 4.2, 4.3 and 4.5).

Discontinuation of moderate-to-strong CYP3A inducers and moderate-to-strong CYP2C9 inducers may lead to increased blood concentrations of aficamten, and increase the risk of heart failure due to systolic dysfunction. Conversely, initiation of certain medicinal products that induce P450s (e.g. rifampicin, moderate-to-strong CYP3A or CYP2C9 inducers) may lead to decreased blood concentrations of aficamten and potential loss of effectiveness (see sections 4.2, 4.3 and 4.5).

Patients should be advised of the potential for drug interactions and to inform their healthcare professional of all concomitant medicinal products prior to and during MYQORZO treatment.

Pregnancy

There is no evidence for the use of aficamten in pregnant women, and animal studies are insufficient to inform maternal or embryo-foetal risk in humans. Foetal harm cannot be ruled out (see sections 4.6 and 5.3).

Recurrence of HCM symptoms with discontinuation

Discontinuation of aficamten may result in recurrence of HCM symptoms. In SEQUOIA-HCM, cardiovascular adverse events were reported more commonly in the aficamten group compared to the placebo group with an onset during the washout period [n=23 (16.2%) versus n=9 (6.5%)], 3 had serious events of worsening HCM when stopping aficamten. Careful monitoring during discontinuation is recommended. Gradual dose reduction may attenuate the rate of symptom recurrence following treatment discontinuation (see section 4.2).

Excipient with known effect

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

Pharmacodynamic interactions

If a treatment with negative inotrope effect, such as non-dihydropyridine calcium channel blockers or disopyramide, is initiated, or if the dose of a medicinal product with negative inotrope effect is increased in a patient receiving aficamten, close medical supervision and monitoring of LVEF should be provided until stable doses and clinical response have been achieved (see section 4.2).

Pharmacokinetic interactions

Effect of other medicinal products on aficamten

Aficamten is primarily metabolised by CYP2C9 and, to a lesser extent by CYP2D6 and CYP3A, with minimal CYP2C19 involvement. Concomitant administration of certain medicinal products that inhibit multiple P450 pathways of aficamten elimination, strong inhibitors of CYP2C9, and moderate-to-strong inducers of CYP2C9 or CYP3A, may affect the exposure of aficamten (see Table 3).

Concomitant use contraindicated

Coadministration of aficamten with more than a single dose of fluconazole and adagrasib is contraindicated (see section 4.3). Fluconazole (400 mg once daily), which is a moderate CYP2C9, strong CYP2C19, and moderate CYP3A inhibitor) increased aficamten AUC by 278%. Adagrasib a moderate CYP2C9, strong inhibitor of CYP3A4 and moderate inhibitor of CYP2D6 is expected to result in comparable or higher increased aficamten exposures as fluconazole.

Coadministration of aficamten with medicinal products that are strong inducers of CYP3A and are also moderate CYP2C9 inducers such as rifampicin or St. John's wort (Hypericum perforatum) may result in decreased plasma concentrations of aficamten leading to loss of therapeutic effect (see section 4.3).

Concomitant use not recommended

Avoidance is recommended for strong CYP2C9 inhibitors (e.g. sulfaphenazole) (see section 4.2).

Other interactions

Interactions of aficamten and potential co-administered medicinal products are listed in Table 3 below (increase is indicated as “↑”, decrease as “↓”). These interactions are based on either drug interaction studies or physiologically based pharmacokinetic predicted interactions due to the expected magnitude of interaction.

Table 3: Interactions between aficamten and other medicinal products

Effect of aficamten on other medicinal products

Coadministration of aficamten is not expected to cause clinically significant drug-drug interactions with sensitive substrates of CYP enzymes or drug transporters.

Aficamten increased total dabigatran exposure by 26% and therefore, aficamten is not a clinically significant P-glycoprotein inhibitor.

Women of childbearing potential

Women of childbearing potential have to use effective contraception during treatment.

Pregnancy

There is no evidence from the use of aficamten in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). A careful benefit/risk evaluation is required before use and during pregnancy and MYQORZO should not be used during pregnancy unless the clinical condition of the woman requires treatment with aficamten.

Based on the mode of action of aficamten, a negative inotropic effect on the foetal heart cannot be ruled out. If a woman is treated with aficamten during pregnancy, regular foetal echocardiography (e.g. every 2 weeks) is recommended. Dose reduction or discontinuation of aficamten should be considered if any sign of foetal cardiac dysfunction is observed, also considering the maternal half-life of aficamten (approximately 3.3 days, see section 5.2). Monitoring of the woman should consider the circulatory adaptations to pregnancy.

Breast-feeding

It is unknown whether aficamten/metabolites are excreted in human milk. There is insufficient information on the excretion of aficamten/metabolites in animal milk and a risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from MYQORZO therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

No human fertility data on aficamten are available. No effects on fertility were observed in animal studies.

Aficamten has minor influence on the ability to drive and use machines. Dizziness may occur during use of aficamten. Patients should be advised not to drive or use machines if they experience dizziness.

Summary of the safety profile

The most commonly reported adverse reactions observed with aficamten are dizziness (4.2%), systolic dysfunction defined as LVEF < 50% (3.5%), palpitations (7%) and hypertension (7.7%).

Tabulated list of adverse reactions

The frequencies of adverse reactions are based on all-cause adverse events frequencies of 142 patients exposed to aficamten in SEQUOIA-HCM study (see section 5.1) with a median treatment duration of 24.1 weeks (range 3.9 to 29.4 weeks).

The adverse reactions included in Table 4 are listed according to system organ class in MedDRA. Within each system organ class, the adverse reactions are presented in order of decreasing frequency and seriousness. In addition, the corresponding frequency category for each adverse reaction is defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000).

Table 4: Adverse reactions

¹ Defined as LVEF < 50% with or without symptoms.

Description of selected adverse reactions

Systolic dysfunction

In SEQUOIA-HCM study, during the 24-week treatment period, 3.5% patients in the aficamten group experienced a reversible dose related reduction in LVEF to < 50% (median 47%; range 34% to 49%). One patient in the aficamten group experienced an asymptomatic LVEF < 40%. Reductions in LVEF to < 50% did not require treatment interruption and were not associated with clinical heart failure (see section 4.4).

Effects on blood pressure

In SEQUOIA-HCM, adverse events of hypertension were reported more commonly in the aficamten group compared with the placebo group (7.7% versus 2.1%). The mean increases of blood pressure associated with aficamten treatment were 2.3 mmHg for systolic blood pressure, and 3.1 mmHg for diastolic blood pressure. Most reports of hypertension were in patients with a history of hypertension, and all reports were non-serious and mild or moderate in severity. Aficamten-associated increases in blood pressure are thought to be a consequence of relief of LVOT obstruction with improved cardiac output.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

The highest single dose of aficamten 75 mg was administered to 1 healthy participant and resulted in LVEF of 35% at 1.5 hours post-dose that was asymptomatic, with recovery to LVEF of 52% at 4 hours post-dose. Treatment of overdose with consists of discontinuation of aficamten as well as medically supportive measures to maintain hemodynamic stability, including close monitoring of vital signs and LVEF and management of the clinical status of the patient. Overdose in humans can be life-threatening and result in asystole refractory to any medical intervention.

Pharmacotherapeutic group: Cardiac therapy, Other cardiac preparations, ATC code: Not yet assigned

Mechanism of action

Aficamten is a reversible allosteric cardiac myosin inhibitor that binds directly to the motor domain of cardiac myosin and prevents it from entering the force-producing state. Nonclinical data indicate that aficamten is selective for the cardiac isoform of myosin compared to fast skeletal myosin. Specifically, aficamten inhibited bovine cardiac myofibrillar ATPase with approximately 5-fold higher potency than rabbit fast skeletal myofibrillar ATPase. It is designed to reduce the hypercontractility in the cardiac sarcomere fundamental to the pathophysiology of HCM. The consequent reduction in cardiac contractility reduces LVOT obstruction in HCM patients.

Pharmacodynamic effects

LVEF

In SEQUOIA-HCM study, the mean [standard deviation (SD)] resting LVEF at baseline was 74.8% (5.5%) for patients in the aficamten group and 74.8% (6.3%) in the placebo group. Consistent with the mechanism of action of aficamten, least squares (LS) mean [standard error (SE)] change from baseline in LVEF was -6.8% (0.6%) in the aficamten group and -2% (0.6%) in the placebo group at the end of the 24-week treatment period. Mean LVEF was similar between the aficamten and placebo groups 4 weeks after the end of treatment.

LVOT obstruction

In SEQUOIA-HCM study, the mean (SD) resting and Valsalva LVOT‑G at baseline were 54.8 (27) and 82.9 (32) mmHg for patients in the aficamten group and 55.3 (32.2) and 83.3 (32.7) mmHg in the placebo group. At week 24, the LS mean (SE) changes from baseline in resting and Valsalva LVOT‑G were -35.8 (2.1) mmHg and -48.1 (2.4) mmHg, respectively, for the aficamten group and 4.1(2.1) mmHg and 2.2 (2.4) mmHg respectively for the placebo group. Valsalva LVOT‑G were similar to baseline for both treatment arms 4 weeks after the discontinuation from treatment.

Cardiac biomarkers

In SEQUOIA-HCM, geometric mean NT-proBNP and troponin I at baseline were 734.7 pg/mL and 17.1 ng/L for patients in the aficamten group and 709.8 pg/mL and 16.6 ng/L in the placebo group. At week 24, the proportional change from based in NT-proBNP and troponin I were 0.19 and 0.58, respectively, for the aficamten group and 0.99 and 1.01, respectively, for the placebo group. NT-proBNP and troponin I were similar to baseline for both treatment arms 4 weeks after the discontinuation from treatment.

Cardiac electrophysiology

The results of a thorough QT study demonstrated a lack of QTc prolongation across the therapeutic concentration range of aficamten. At a single dose of 50 mg (similar exposure as 20 mg daily dosing to steady-state), the upper limits of the predicted placebo-corrected change from baseline in QT interval corrected by Fridericia (ΔΔQTcF) 90% confidence interval for aficamten were all < 10 msec.

Clinical efficacy and safety

The efficacy of aficamten was evaluated in SEQUOIA-HCM study, a phase 3, multicentre, randomised, double-blind, placebo-controlled study in 282 adults (142 aficamten, 140 placebo) with symptomatic NYHA class II and III oHCM, LVEF ≥ 60%, and resting and peak Valsalva LVOT‑G ≥ 30 and ≥ 50 mmHg at screening, respectively.

Patients with a known infiltrative or storage disorder causing cardiac hypertrophy such as Noonan syndrome, Fabry disease or amyloidosis were excluded.

Patients were randomised in a 1:1 ratio to receive either a starting dose of 5 mg of aficamten or placebo once daily for 24 weeks. Stratification factors included baseline use of beta blockers and cardiopulmonary exercise testing (CPET) ergometer (treadmill or cycle). At baseline, beta-blockers were used by 61.3% of patients, and non-dihydropyridine calcium channel blockers were used by 28.7% of participants. In addition, 12.8% of patients were taking disopyramide. Overall, 14.5% of patients were not taking any background medicinal product at baseline.

Overall, baseline demographics and disease characteristics were balanced between treatment groups. The study enrolled patients with a mean age of 59.1 years; (range 18 to 84 years), 59% male, 79% White, 19% Asian and 1% Black or African American. The mean, body mass index was 28.1 kg/m², mean resting heart rate of 66 bpm and mean blood pressure of 125/74 mmHg. In SEQUOIA-HCM there were 57 patients aged 65 years and older. No patients had undergone prior septal reduction therapy (SRT). At baseline, 76% of the randomised patients were NYHA class II and 24% were NYHA class III. The median LVEF was 75.6%, the mean resting LVOT‑G was 55.1 mmHg, the mean Valsalva LVOT‑G was 83.1 mmHg, and the mean Kansas City Cardiomyopathy Questionnaire – Clinical Summary Score (KCCQ-CSS) was 74.7.

Patients were initiated on aficamten at a dose of 5 mg once daily. Doses were individually titrated at weeks 2, 4 and 6 if Valsalva LVOT‑G ≥ 30 mmHg and LVEF ≥ 55% in 5 mg intervals up to a maximum dose of 20 mg one daily. At week 24 in the aficamten group, 46% of patients were receiving a 20 mg dose, 35% were receiving a 15 mg dose, 15.3% were receiving a 10 mg dose and 3.6% were receiving a 5 mg dose.

Primary endpoint - peak oxygen uptake (pVO₂)

In SEQUOIA-HCM study, the primary endpoint of change from baseline in pVO₂ to week 24 was statistically significant and greater in the aficamten group compared with placebo, as shown in Table 5.

Secondary endpoints

The treatment effects of aficamten on health status, functional capacity, and LVOT obstruction were assessed by change in KCCQ-CSS, proportion of patients with ≥ 1 class improvement in NYHA functional class, change from baseline in Valsalva LVOT‑G, proportion of patients with Valsalva LVOT‑G ≤ 30 mmHg and duration of eligibility for septal reduction therapy (SRT). At week 24, patients receiving aficamten had greater improvement compared to the placebo group across all secondary points (Table 5).

A range of demographic characteristics, baseline disease characteristics, and baseline concomitant medicinal products (e.g. use of beta blockers) were examined for their influence on outcomes. Results of the primary analysis favoured aficamten consistently across all subgroups.

The effect of aficamten on the left ventricular outflow tract gradient after the Valsalva maneuver was relatively rapid, with a LS mean difference between the groups of −20 mm Hg (95% CI, −27.3 to −13.3) after 2 weeks.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with MYQORZO in one or more subsets of the paediatric population in the treatment of hypertrophic cardiomyopathy (see section 4.2 for information on paediatric use).

Aficamten exposure increases dose proportionally following multiple once-daily doses of 1 mg to 75 mg of aficamten. Aficamten pharmacokinetics was comparable between healthy participants and patients with oHCM: healthy participants demonstrated only 23% lower exposure than patients with oHCM. Geometric mean accumulation ratios for aficamten were similar across dose levels and ranged from 4.57 to 4.82.

Absorption

Aficamten is rapidly absorbed with a median time to maximum concentration (t_max) of 1.5 to 2 hours. Aficamten maximum concentration (C_max) and trough concentration (C_trough) after 20 mg once daily administration at steady-state were 336 and 288 ng/mL, respectively. The bioavailability of aficamten after oral administration is unknown. No clinically significant differences in aficamten AUC and C_max were observed following its administration with a high-fat, high-calorie meal.

Distribution

Aficamten is approximately 90% bound to plasma proteins and demonstrates apparent volume of distribution of 309 L. The blood to plasma ratio of aficamten was 0.94.

Biotransformation

Aficamten is extensively metabolised in humans, primarily through CYP2C9 (50%) with contributions by CYP3A (26%) and CYP2D6 (21%), and minimal involvement of CYP2C19 (3%). Aficamten is primarily metabolised to 2 pharmacologically inactive metabolites, CK-3834282 and CK-3834283, that circulate at approximately 56% and 103% of parent in plasma, respectively.

CYP2C9 is a polymorphic enzyme. Literature data indicate that CYP2C9*2*3 and especially CYP2C9*3*3 variants result in less activity. Those variants still have 15-45% of the activity of normal metabolisers as demonstrated on the pharmacokinetics of several sensitive substrates. Since aficamten is also metabolised by CYP enzymes other than CYP2C9, and some CYP2C9 activity is remaining in patients with CYP2C9 poor metaboliser phenotype, no genotyping, nor genotype-dependent starting dose, is considered necessary.

Elimination

Aficamten has a median terminal half-life (t_½) and time to steady-state of approximately 80 hours and 17 days, respectively, in patients with oHCM. Most (~95%) patients with oHCM are expected to have a t_½ of less than 155 hours and to achieve steady-state by 33 days of daily aficamten dosing. At steady-state, the peak-to-trough plasma concentration ratio with once daily dosing is approximately 1.2. The total clearance is 2.6 L/h and the renal clearance is < 0.1% of total clearance.

Following a single 20 mg radiolabeled dose of aficamten, 32% (0.055% unchanged aficamten) was excreted in urine and 58% (5% unchanged aficamten) was excreted in faeces.

Special populations

Population pharmacokinetic analyses demonstrated no clinically meaningful differences in the pharmacokinetics of aficamten were observed based on age (18 to 83 years) or ethnicity.

Small but significant differences in aficamten exposure with sex and body weight were observed. Female patients demonstrated a 31% higher exposure than male patients. The highest body weight quartile of patients (105 kg) demonstrated a 44% lower aficamten exposure than the lowest body weight quartile of patients (64 kg).

Renal impairment

Population pharmacokinetic analyses demonstrated no clinically meaningful differences in the pharmacokinetics of aficamten (14 to 28% increase in exposure) based on mild to moderate (eGFR ≥ 30 mL/min) renal impairment. The effects of severe (eGFR < 30 mL/min) renal impairment are unknown.

Hepatic impairment

Based on phase 1 study, no clinically meaningful differences in the pharmacokinetics of aficamten in mild (Child-Pugh class A) to moderate (Child-Pugh class B) hepatic impairment are expected. Moderate hepatic impairment demonstrated no change in aficamten exposure. The effects of severe (Child-Pugh class C) hepatic impairment are unknown.

Paediatric population

The pharmacokinetics of aficamten have not been investigated in patients below 18 years of age.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential.

Embryo-foetal and postnatal development

When aficamten was administered orally in an embryo-foetal toxicity study in the rat, increases in the number of early and late resorptions, decreases in group mean foetal body weight, and foetal abnormalities such as short tail (1 foetus) and kinked tail (2 foetuses) were observed at maternally toxic exposures 2.5x above the maximum recommended human dose (MRHD) of 20 mg of aficamten based on AUC. There were no aficamten-associated adverse effects on foetal growth, or foetal external or visceral variations observed at exposures 1.9x above the MRHD based on AUC.

When aficamten was administered orally in an embryo-foetal toxicity study in the rabbit, increases in the number of late resorptions were observed at maternally toxic exposures below the MRHD. As such this study is considered insufficient.

In a pre- and postnatal development study, aficamten was administered to maternal rats at doses up to 6 mg/kg/day during organogenesis through delivery and weaning, which is anticipated to be at an exposure close to the MRHD. At 6 mg/kg/day there were reductions in maternal body weight, increased heart weight, a reduction in the viability index in the pups, decreased mean group body weight, suspected dehydration, no milk band present and bent tail. At the NOAEL of 1.5 mg/kg/day there were no maternal effects and no effects in the offspring on sexual maturation, neurobehavioral or reproductive function parameters in the rat offspring. At these doses, no drug-related evidence of teratogenic potential was observed.

Tablet core

Microcrystalline cellulose (E 460(i))

Mannitol (E 421)

Croscarmellose sodium (E 468)

Hydroxypropylcellulose (E 463)

Sodium laurilsulfate

Magnesium stearate (E 470b)

Film coating

Macrogol poly(vinyl alcohol) grafted copolymer (E 1209)

Talc (E 553b)

Titanium dioxide (E 171)

Glycerol mono and dicaprylocaprate (E 471)

Poly(vinyl alcohol) (E 1203)

Indigo carmine aluminum lake (E 132)

Carmine (E 120)

Not applicable.

30 months

Store below 30 °C.

Polyvinylchloride (PVC)/Aluminium foil blister containing 14 film-coated tablets.

Pack sizes of 14, 28, or 98 tablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.