CAMZYOS 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, patients’ left ventricular ejection fraction (LVEF) should be assessed by echocardiography (see section 4.4). If LVEF is < 55%, treatment should not be initiated.

Before initiation of treatment, women of childbearing potential must have a negative pregnancy test (see section 4.4 and 4.6).

Patients should be genotyped for Cytochrome P450 (CYP) 2C19 (CYP2C19) in order to determine appropriate mavacamten dose. Patients with CYP2C19 poor metabolizer phenotype may have increased mavacamten exposures (up to 3 times) that can lead to increased risk of systolic dysfunction compared to normal metabolizers (see section 4.4 and 5.2). If treatment initiation occurs prior to determination of CYP2C19 phenotype, patients should follow dosing instructions for poor metabolisers (see figure 1 and table 1) until CYP2C19 phenotype is determined.

Posology

The dose range is 2.5 mg to 15 mg (either 2.5 mg, 5 mg, 10 mg or 15 mg). The bioequivalence between strengths has not been confirmed in a bioequivalence study in humans; therefore, the use of multiple capsules to achieve a prescribed dose is prohibited and one capsule of the appropriate dose strength should be used.

CYP2C19 poor metaboliser phenotype

The recommended starting dose is 2.5 mg orally once daily. The maximum dose is 5 mg once daily. The patient should be assessed for early clinical response by left ventricular outflow tract (LVOT) gradient with Valsalva manoeuvre 4 and 8 weeks after treatment initiation (see figure 1).

CYP2C19 intermediate, normal, rapid and ultra‑rapid metaboliser phenotype

The recommended starting dose is 5 mg orally once daily. The maximum dose is 15 mg once daily. The patient should be assessed for early clinical response by LVOT gradient with Valsalva manoeuvre 4 and 8 weeks after treatment initiation (see figure 2).

Once an individualised maintenance dose is achieved, patients should be assessed every 12 weeks (see figure 3). If at any visit the patient’s LVEF is < 50%, the treatment should be interrupted for 4 weeks and until LVEF returns to ≥ 50% (see figure 4).

In patients experiencing an intercurrent illness such as serious infection or arrhythmia (including atrial fibrillation or other uncontrolled tachyarrhythmia) which may impair systolic function, LVEF assessment is recommended, and dose increases are not recommended until intercurrent illness is resolved (see section 4.4).

Consideration should be given to discontinue treatment in patients who have shown no response (e.g., no improvement in symptoms, quality of life, exercise capacity, LVOT gradient) after 4‑6 months on the maximum tolerated dose.

* Interrupt treatment if LVEF is < 50% at any clinical visit; restart treatment after 4 weeks if LVEF ≥ 50% (see figure 4).

LVEF = left ventricular ejection fraction; LVOT = left ventricular outflow tract

* Interrupt treatment if LVEF is < 50% at any clinical visit; restart treatment after 4 weeks if LVEF ≥ 50% (see figure 4).

LVEF = left ventricular ejection fraction; LVOT = left ventricular outflow tract

LVEF = left ventricular ejection fraction; LVOT = left ventricular outflow tract

LVEF = left ventricular ejection fraction; LVOT = left ventricular outflow tract

Dose modification with concomitant medicinal products

For concomitant treatment with inhibitors and inducers of CYP2C19 or CYP3A4, follow the steps shown in table 1 (see also section 4.5).

Table 1:           Dose modification of mavacamten with concomitant medicinal products

* includes patients for whom the CYP2C19 phenotype has not yet been determined.

Missed or delayed doses

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

Special populations

Elderly

No dose adjustment to the standard dose and titration scheme is required for patients aged 65 years and older (see section 5.2).

Renal impairment

No dose adjustment to the standard dose and titration scheme is required for patients with mild (estimated glomerular filtration rate [eGFR] 60‑89 mL/min/1.73m²) to moderate (eGFR 30‑59 mL/min/1.73m²) renal impairment. No dose recommendation can be made for patients with severe (eGFR < 30 mL/min/1.73m²) renal impairment because mavacamten has not been studied in patients with severe renal impairment (see section 5.2).

Hepatic impairment

The mavacamten starting dose should be 2.5 mg in all patients with mild (Child-Pugh class A) and moderate (Child-Pugh class B) hepatic impairment since mavacamten exposure is likely to be increased (see section 5.2). No dose recommendation can be made for patients with severe hepatic impairment (Child-Pugh class C) because mavacamten has not been studied in patients with severe hepatic impairment (see section 4.4 and 5.2).

Paediatric population

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

Mavacamten should not be used in children less than 12 years because of potential safety concerns.

Method of administration

For oral use.

Treatment should be taken once daily with or without meals at about the same time each day. Use a single capsule for a prescribed dose. The capsule should be swallowed whole with water.

Systolic dysfunction defined as symptomatic LVEF < 50%

Mavacamten reduces LVEF and may cause heart failure due to systolic dysfunction defined as symptomatic LVEF < 50%. Patients with a serious intercurrent illness such as infection or arrhythmia (including atrial fibrillation or other uncontrolled tachyarrhythmia), or those undergoing major cardiac surgery may be at greater risk of systolic dysfunction and progress to heart failure (see section 4.8). New or worsening dyspnoea, chest pain, fatigue, palpitations, leg oedema or elevations in N-terminal pro‑B‑type natriuretic peptide (NT‑proBNP) may be signs and symptoms of systolic dysfunction and should prompt an evaluation of cardiac function. LVEF should be measured prior to initiating treatment and closely monitored thereafter. Treatment interruption may be necessary to ensure that LVEF remains ≥ 50% (see section 4.2).

Heart failure risk or loss of response to mavacamten due to interactions

Mavacamten is primarily metabolised by CYP2C19 and to a lesser extent by CYP3A4 and mostly by CYP3A4 in CYP2C19 poor metabolisers, which may lead to the following interactions (see section 4.5):

§    Starting or increasing the dose of a strong or moderate CYP3A4 inhibitor or any CYP2C19 inhibitor may increase risk of heart failure due to systolic dysfunction.

§    Stopping or decreasing dose of any inhibitor of CYP3A4 or CYP2C19 may lead to a loss of therapeutic response to mavacamten.

§    Starting a strong CYP3A4 or strong CYP2C19 inducer may lead to a loss of therapeutic response to mavacamten.

§    Stopping a strong CYP3A4 or strong CYP2C19 inducer may increase risk of heart failure due to systolic dysfunction.

Prior to and during mavacamten treatment, the potential for interactions, including over the counter medicinal products (such as omeprazole or esomeprazole), should be considered.

§    Concomitant treatment with strong CYP3A4 inhibitors in patients with CYP2C19 poor metaboliser phenotype and undetermined CYP2C19 phenotype is contraindicated (see section 4.3).

§    Concomitant treatment with the combination of a strong CYP2C19 inhibitor and a strong CYP3A4 inhibitor is contraindicated (see section 4.3)

§    Dose adjustment of mavacamten and/or close monitoring may be required in patients initiating or discontinuing treatment with, or changing the dose of concomitant medicinal products that are inhibitors or inducers of CYP2C19 or CYP3A4 (see section 4.2 and 4.5). Intermittent administration of these medicinal products is not recommended (see section 4.5).

Concomitant use of negative inotropes

The safety of concomitant use of mavacamten with disopyramide, or use of mavacamten in patients taking beta blockers in combination with verapamil or diltiazem has not been established. Therefore, patients should be closely monitored when taking these concomitant medicinal products (see section 4.5).

Embryo-foetal toxicity

Based on animal studies, mavacamten is suspected to cause embryo-foetal toxicity when administered to a pregnant woman (see section 5.3). Due to risk to the foetus, CAMZYOS is contraindicated during pregnancy and in women of childbearing potential not using effective contraception. Before initiation of treatment, women of childbearing potential must be informed of this risk to the foetus, must have a negative pregnancy test and must use effective contraception during treatment and for 6 months after treatment discontinuation (see sections 4.3 and 4.6).

Sodium content

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

Pharmacodynamic interactions

If treatment with a new negative inotrope is initiated or if the dose of a negative inotrope is increased in a patient receiving mavacamten, close medical supervision with monitoring of LVEF should be provided until stable doses and clinical response have been achieved (see section 4.2 and 4.4).

Pharmacokinetic interactions

Effect of other medicinal products on mavacamten

In CYP2C19 intermediate, normal, rapid and ultra‑rapid metabolisers, mavacamten is primarily metabolised by CYP2C19 and to a lesser extent by CYP3A4. In CYP2C19 poor metabolisers, metabolism is mostly by CYP3A4 (see section 5.2). CYP2C19 inhibitors/inducers and CYP3A4 inhibitors/inducers may thus affect the clearance of mavacamten and increase/decrease mavacamten plasma concentration, and this will depend on the CYP2C19 phenotype.

All clinical drug-drug interaction studies mainly enrolled CYP2C19 normal metabolisers and no CYP2C19 poor metabolisers were included in the assessment of the drug‑drug interaction and therefore the effect of co‑administration of CYP2C19 and CYP3A4 inhibitors with mavacamten in CYP2C19 poor metabolisers is not completely certain.

Recommendations for dose modification and/or additional monitoring of patients initiating or discontinuing treatment with, or changing the dose of, concomitant medicinal products that are inhibitors of CYP2C19 or CYP3A4 or inducers of CYP2C19 or CYP3A4 are provided in table 2.

Strong CYP2C19 plus strong CYP3A4 inhibitors

Co‑administration of mavacamten with the combination of a strong CYP2C19 and a strong CYP3A4 inhibitor is contra‑indicated (see section 4.3).

CYP2C19 inhibitors

The effect of a moderate and strong CYP2C19 inhibitor on the PK of mavacamten was not investigated in a clinical drug‑drug interaction study. The effect of a strong CYP2C19 inhibitor (e.g., ticlopidine) will be similar to the effect of the CYP2C19 poor metabolising status (see table 1).

Co‑administration of mavacamten with a weak CYP2C19 inhibitor (omeprazole) resulted in a 48% increase in mavacamten AUC_inf with no effect on C_max in CYP2C19 normal metabolisers.

Intermittent administration of a CYP2C19 inhibitor (such as omeprazole or esomeprazole) is not recommended (see section 4.4).

CYP3A4 inhibitors

Co‑administration of mavacamten with a strong CYP3A4 inhibitor (itraconazole) in CYP2C19 normal metabolisers resulted in an increase in mavacamten plasma concentration of up to 59% and 40% in AUC_0‑24 and C_max, respectively.

Co‑administration of mavacamten with a moderate CYP3A4 inhibitor (verapamil) in CYP2C19 normal metabolisers resulted in an increase in mavacamten plasma concentration of 16% and 52% in AUC_inf and C_max, respectively. This change was not considered clinically significant.

CYP2C19 and CYP3A4 inducers

No clinical interaction studies were conducted to investigate the effect of concomitant administration with a strong CYP3A4 and CYP2C19 inducer. Co‑administration of mavacamten with a strong inducer of both CYP2C19 and CYP3A4 (e.g., rifampicin) is expected to significantly affect the pharmacokinetics (PK) of mavacamten and leads to reduced efficacy and therefore co‑administration with strong inducers of both CYP2C19 and CYP3A4 is not recommended. If discontinuing concomitant treatment with a strong inducer of CYP2C19 or CYP3A4 increase clinical assessments and mavacamten dose should be reduced (see section 4.2).

Table 2:           Dose modification/monitoring of mavacamten with concomitant medicinal products

* Includes patients for whom the CYP2C19 phenotype has not yet been determined.

^a Omeprazole is considered a weak CYP2C19 inhibitor at a dose of 20 mg once daily and a moderate CYP2C19 inhibitor at a total daily dose of 40 mg.

Effect of mavacamten on other medicinal products

Mavacamten in vitro data suggest a potential induction of CYP3A4 substrates. Co‑administration of a 17‑day course of mavacamten at clinical relevant exposures in CYP2C19 normal, rapid and ultra‑rapid metabolisers did not decrease the exposure to ethinyl oestradiol and norethindrone, which are the components of typical oral contraceptives and substrates for CYP3A4. Furthermore, co‑administration of a 16‑day course of mavacamten in CYP2C19 normal metabolisers, at clinical relevant exposures, resulted in a 13% decrease in midazolam plasma concentration. This change was not considered clinically significant.

Women of childbearing potential / Contraception in females

CAMZYOS is contraindicated in women of childbearing potential not using effective contraception (see section 4.3). Therefore, before initiation of treatment in women of childbearing potential, a negative pregnancy test result must be available and counselling should be provided regarding the serious risk to the foetus. Women of childbearing potential must use effective contraception during treatment and for 6 months after discontinuation of CAMZYOS, since it takes approximately 5 half‑lives (approximately 45 days for CYP2C19 normal metabolisers and 115 days for CYP2C19 poor metabolisers) to eliminate mavacamten from the body after treatment discontinuation (see sections 4.4 and 5.2).

When stopping mavacamten therapy for planning a pregnancy the possible return of LVOT obstruction and symptom burden should be considered (see section 4.4).

Pregnancy

There are no data from the use of mavacamten in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Mavacamten is suspected to cause embryo-foetal toxicity when administered during pregnancy. Therefore, CAMZYOS is contraindicated during pregnancy (see section 4.3). CAMZYOS should be stopped 6 months before planning a pregnancy (see section 4.4). If a patient becomes pregnant, mavacamten must be discontinued. Medical advice should be given regarding the risk of harmful effects to the foetus associated with treatment and ultrasonography examinations should be performed.

Breast-feeding

It is unknown whether mavacamten or its metabolites are excreted in human milk. There is no information on the excretion of mavacamten or its metabolites in animal milk (see section 5.3). Because of the unknown adverse effects of mavacamten in breastfed newborns/infants, women must not breast-feed during treatment with mavacamten.

Fertility

No human fertility data on mavacamten are available. Studies in animals are insufficient with respect to male or female fertility (see section 5.3).

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

4.8.1 Adverse reactions

Summary of the safety profile

The most commonly reported adverse reactions with mavacamten are dizziness (17%), dyspnoea (12%), systolic dysfunction (5%) and syncope (5%).

Tabulated list of adverse reactions

Adverse reactions reported in patients treated with mavacamten in two phase 3 studies are tabulated below. A total of 179 patients received a daily dose of either 2.5 mg, 5 mg, 10 mg or 15 mg of mavacamten. The median treatment duration for patients receiving mavacamten was 30.1 weeks (range: 1.6 to 40.3 weeks).

The adverse reactions included in table 3 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 3:           Adverse reactions

^a Defined as LVEF < 50% with or without symptoms.

Description of selected adverse reactions

Systolic dysfunction

In Phase 3 clinical studies, 5% (9/179) of patients in the mavacamten group experienced reversible reductions in LVEF < 50% (median 45%: range: 35‑49%) while on treatment. In 56% (5/9) of these patients, reductions were observed without other clinical manifestations. In all patients treated with mavacamten, LVEF recovered following interruption of mavacamten and they completed the study on treatment (see section 4.4).

Dyspnoea

In Phase 3 clinical studies, dyspnoea was reported in 12.3% of patients treated with mavacamten compared to 8.7% of patients on placebo. In the EXPLORER-HCM study, most (67%) of the dyspnoea events were reported after mavacamten was discontinued, with median time to onset of 2 weeks (range: 0.1‑4.9) after last dose.

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.

To report any side effect(s):

·         Saudi Arabia:

·         Other GCC States:

Human experience of overdose with mavacamten is limited. Mavacamten has been given as a single dose of up to 144 mg in patients with HCM. There was one serious adverse reaction of vasovagal reaction, hypotension, and asystole lasting 38 seconds reported at that dose. In healthy subjects, doses of up to 25 mg have been administered for up to 25 days. A reduction of LVEF by 20% or greater was experienced in 3 out of 8 participants treated at the 25 mg dose level. Systolic dysfunction is the most likely result of overdose of mavacamten. If warranted, treatment of overdose with mavacamten consists of discontinuation of mavacamten treatment as well as medically supportive measures to maintain hemodynamic status (e.g. initiation of inotropic support with adrenergic agents), including close monitoring of vital signs and LVEF and management of the clinical status of the patient. Early administration of activated charcoal may be considered in case of mavacamten overdose to reduce absorption. This recommendation is based on standard treatment of medicinal product overdose, as the use of activated charcoal to reduce absorption of mavacamten has not been specifically studied.

Pharmacotherapeutic group: Cardiac therapy, Other cardiac preparations, ATC code: C01EB24

Mechanism of action

Mavacamten is a selective, allosteric, and reversible cardiac myosin inhibitor. Mavacamten modulates the number of myosin heads that can enter power-generating states, thus reducing (or in HCM normalizing) the probability of force-producing systolic and residual diastolic cross-bridge formation. Mavacamten also shifts the overall myosin population towards an energy-sparing, but recruitable, super-relaxed state. Excess cross-bridge formation and dysregulation of the super-relaxed state of myosin are mechanistic hallmarks of HCM, which can result in hyper-contractility, impaired relaxation, excess energy consumption, and myocardial wall stress. In HCM patients, cardiac myosin inhibition with mavacamten normalises contractility, reduces dynamic LVOT obstruction, and improves cardiac filling pressures.

Pharmacodynamic effects

LVEF

In the EXPLORER-HCM study, mean (SD) resting LVEF was 74% (6) at baseline in both treatment arms, reductions in mean absolute change from baseline in LVEF was ‑4% (95% CI: ‑5.3, ‑2.5) in the mavacamten arm and 0% (95% CI: ‑1.2, 1.0) in the placebo arm over the 30‑week treatment period. At Week 38, following an 8‑week interruption of mavacamten, mean LVEF was similar to baseline for both treatment arms.

LVOT obstruction

In the EXPLORER-HCM study, patients achieved reductions in mean resting and provoked (Valsalva) LVOT gradient by week 4 which were sustained throughout the 30‑week study duration. At week 30, the mean change from baseline in resting and Valsalva LVOT gradients were ‑39 (95% CI: ‑44.0, ‑33.2) mmHg and ‑49 (95% CI: ‑55.4, ‑43.0) mmHg, respectively, for mavacamten arm and ‑6 (95% CI: ‑10.5, ‑0.5) mmHg and ‑12 (95% CI: ‑17.6, ‑6.6) mmHg, respectively, for the placebo arm. At week 38, following 8 weeks of mavacamten washout, mean LVEF and LVOT gradients were similar to baseline for both treatment arms.

Cardiac electrophysiology

In HCM, the QT interval may be intrinsically prolonged due to the underlying disease, in association with ventricular pacing, or in association with medicinal products with potential for QT prolongation commonly used in the HCM population. An exposure-response analysis across all clinical studies in HCM patients has shown a concentration-dependent shortening of the QTcF interval with mavacamten. The mean placebo corrected change from baseline in oHCM patients was ‑8.7 ms (upper and lower limit of the 90% CI ‑6.7 ms and ‑10.8 ms, respectively) at the median steady-state C_max of 452 ng/mL. Patients with longer baseline QTcF intervals tended to display the greatest shortening.

Consistent with nonclinical findings in normal hearts, in one clinical study in healthy subjects sustained exposure to mavacamten at supratherapeutic levels leading to marked depression of systolic function was associated with QTc prolongation (< 20 ms). No acute QTc changes have been observed at comparable (or higher) exposures after single doses. The findings in healthy hearts are attributed to an adaptive response to the cardiac mechanical/functional changes (marked mechanical LV depression) occurring in response to myosin inhibition in hearts with normal physiology and LV contractility.

Clinical efficacy and safety

EXPLORER-HCM

The efficacy of mavacamten was evaluated in a double-blind, randomised, placebo-controlled, parallel-arm, multicentre, international, Phase 3 study enrolling 251 adult patients with NYHA class II and III oHCM, LVEF ≥ 55%, and LVOT peak gradient ≥ 50 mmHg at rest or with provocation at time of oHCM diagnosis and Valsalva LVOT gradient ≥ 30 mmHg at screening. The majority of patients received background HCM treatment for a total of 96% in mavacamten arm (beta blockers 76%, calcium channel blockers 20%) and of 87% in the placebo arm (beta blockers 74%, calcium channel blockers 13%).

Patients were randomised in a 1:1 ratio to receive either a starting dose of 5 mg of mavacamten (123 patients) or matching placebo (128 patients) once daily for 30 weeks. The dose was periodically adjusted to optimise patients’ response (decrease in LVOT gradient with Valsalva manoeuvre), maintain LVEF ≥ 50%, and was also guided by plasma concentrations of mavacamten. Within the dose range of 2.5 mg to 15 mg, a total of 60 patients received 5 mg and 40 patients received 10 mg. During the study, 3 of 7 patients on mavacamten had LVEF < 50% prior to the week 30 visit and temporarily interrupted their dose; 2 patients resumed treatment at the same dose and 1 patient had the dose reduced from 10 mg to 5 mg.

Treatment assignment was stratified by baseline NYHA class (II or III), current treatment with beta blockers (yes or no), and type of ergometer (treadmill or exercise bicycle) used for assessment of peak oxygen consumption (pVO₂). Patients on background dual treatment with beta blocker and calcium channel blocker treatment or disopyramide or ranolazine were excluded. Patients with known infiltrative or storage disorder causing cardiac hypertrophy that mimicked oHCM, such as Fabry disease, amyloidosis, or Noonan syndrome with LV hypertrophy, were also excluded.

The baseline demographic and disease characteristics were balanced between mavacamten and placebo. The mean age was 59 years, 54% (mavacamten) vs 65% (placebo) were male, mean body mass index (BMI) was 30 kg/m², mean heart rate 63 bpm, mean blood pressure 128/76 mmHg, and 90% were Caucasian. At baseline, approximately 73% of randomised subjects were NYHA class II and 27% were NYHA class III. The mean LVEF was 74%, and the mean Valsalva LVOT was 73 mmHg. 8% had prior septal reduction therapy, 75% were on beta -blockers, 17% were on calcium channel blockers, 14% had history of atrial fibrillation, and 23% with implantable cardioverter defibrillator (23%). In EXPLORER-HCM there were 85 patients aged 65 years or older, 45 patients were dosed with mavacamten.

The primary outcome measure included a change at week 30 in exercise capacity measured by pVO₂ and symptoms measured by NYHA functional classification, defined as an improvement of pVO₂ by ≥ 1.5 mL/kg/min and an improvement in NYHA class by at least 1 OR an improvement of pVO₂ by ≥ 3.0 mL/kg/min and no worsening in NYHA class.

A greater proportion of patients treated with mavacamten met the primary and secondary endpoints at week 30 compared to placebo (see table 4).

Table 4:           Analysis of the primary composite and secondary endpoints from EXPLORER‑HCM study

* Least-squares mean difference

† KCCQ-23 CSS = Kansas City Cardiomyopathy Questionnaire‑23 Clinical Summary Score. The KCCQ‑23 CSS is derived from the Total Symptoms Score (TSS) and the Physical Limitations (PL) score of the KCCQ‑23. The CSS ranges from 0 to 100, with higher scores representing better health status. A significant treatment effect on the KCCQ‑23 CSS favouring mavacamten was first observed at week 6 and remained consistent through week 30.

‡ HCMSQ SoB = Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness of Breath. The HCMSQ SoB domain score measures frequency and severity of shortness of breath. The HCMSQ SoB domain score ranges from 0 to 18, with lower scores representing less shortness of breath. A significant treatment effect on the HCMSQ SoB favouring mavacamten was first observed at week 4 and remained consistent through week 30.

A range of demographic characteristics, baseline disease characteristics, and baseline concomitant medicinal products were examined for their influence on outcomes. Results of the primary analysis consistently favoured mavacamten across all subgroups analysed.

VALOR-HCM

The efficacy of mavacamten was evaluated in a Phase 3, double-blind, randomised, 16‑week placebo‑controlled trial in 112 patients with symptomatic oHCM who were septal reduction therapy (SRT) eligible. Patients with severely symptomatic drug-refractory oHCM, and NYHA class III/IV or class II with exertional syncope or near syncope were included in the study. Patients were required to have LVOT peak gradient ≥ 50 mmHg at rest or with provocation, and LVEF ≥ 60%. Patients must have been referred or under active consideration within the past 12 months for SRT and had been actively considering scheduling the procedure.

Patients were randomised 1:1 to receive treatment with mavacamten or placebo once daily. The dose was periodically adjusted within the dose range of 2.5 mg to 15 mg to optimise patient’s response.

The baseline demographic and disease characteristics were balanced between mavacamten and placebo. The mean age was 60.3 years, 51% were male, mean BMI was 31 kg/m², mean heart rate 64 bpm, mean blood pressure 131/74 mmHg, and 89% were Caucasian. At baseline, approximately 7% of randomised subjects were NYHA class II and 92% were NYHA class III. 46% were on beta‑blockers monotherapy, 15% were on calcium channel blockers monotherapy, 33% were on a mixed combination of beta -blockers, calcium channel blockers, and 20% were on disopyramide alone or in combination with other treatment. In VALOR-HCM there were 45 patients aged 65 years or older, 24 patients were dosed with mavacamten.

Mavacamten was shown to be superior to placebo in meeting the primary composite endpoint at week 16 (see table 5). The primary endpoint was a composite of

§    patient decision to proceed with SRT prior to or at week 16 or

§    patients who remain SRT eligible (LVOT gradient of ≥ 50 mmHg and NYHA class III‑IV, or class II with exertional syncope or near syncope) at week 16.

The treatment effects of mavacamten on LVOT obstruction, functional capacity, health status, and cardiac biomarkers were assessed by change from baseline through week 16 in post‑exercise LVOT gradient, proportion of patients with improvement in NYHA class, KCCQ‑23 CSS, NT‑proBNP, and cardiac troponin I. In the VALOR-HCM study, hierarchical testing of secondary efficacy endpoints showed significant improvement in the mavacamten group compared to the placebo group (table 5).

Table 5:           Analysis of the primary composite and secondary endpoints from VALOR-HCM study

^* Least-squares mean difference.

^† KCCQ‑23 CSS=Kansas City Cardiomyopathy Questionnaire‑23 Clinical Summary Score. The KCCQ‑23 CSS is derived from the Total Symptoms Score (TSS) and the Physical Limitations (PL) score of the KCCQ‑23. The CSS ranges from 0 to 100, with higher scores representing better health status.

In the VALOR‑HCM study, secondary endpoint of NT-proBNP, at week 16 (see table 5) showed a sustained reduction from baseline after mavacamten treatment compared to placebo that was similar to that seen in EXPLORER‑HCM at week 30.

Exploratory analysis of left ventricular mass index (LVMI) and left atrial volume index (LAVI) showed reductions in the mavacamten treated patients compared to placebo in EXPLORER-HCM and VALOR‑HCM.

Paediatric population

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

Absorption

Mavacamten is readily absorbed with a median t_max of 1 hour (range: 0.5 to 3 hours) after oral administration with an estimated oral bioavailability of approximately 85% within the clinical dose range. The increase in mavacamten exposure is generally dose proportional after once daily doses of mavacamten (2 mg to 48 mg).

After a single dose of 15 mg mavacamten, C_max and AUC_inf are 47% and 241% higher, respectively, in CYP2C19 poor metabolisers compared to normal metabolisers. Mean half-life is prolonged in CYP2C19 poor metabolisers compared to normal metabolisers (23 days versus 6 to 9 days, respectively).

Inter‑subject PK variability is moderate, with a coefficient of variation for exposure of approximately 30‑50% for C_max and AUC.

A high fat, high calorie meal delayed absorption resulting in a median t_max of 4 hours (range: 0.5 to 8 hours) in the fed state compared to 1 h in the fasted state. Administration with meals resulted in a 12% decrease in AUC_0-inf, however this decrease is not considered clinically significant. Mavacamten may be administered with or without meals.

As mavacamten is titrated based on clinical response (see section 4.2), simulated steady state exposures are summarized using individualised dosage by phenotype (table 6).

Table 6            Simulated average steady state concentration by dose and CYP2C19 phenotype in patients titrated to effect based on Valsalva LVOT and LVEF

Distribution

Plasma protein binding of mavacamten is 97‑98% in clinical studies. The blood‑to‑plasma concentration ratio is 0.79. The apparent volume of distribution (Vd/F) ranged from 114 L to 206 L. Specific studies to assess distribution of mavacamten have not been conducted in humans, however data are consistent with a high volume of distribution.

Based upon 10 male subjects dosed for up to 28 days, the amount of mavacamten distributed to the semen was considered to be low.

Biotransformation

Mavacamten is extensively metabolised, primarily through CYP2C19 (74%), CYP3A4 (18%), and CYP2C9 (7.6%) based on in-vitro reaction phenotyping. Metabolism is expected to be driven through all three pathways, and primarily through CYP2C19 in CYP2C19 intermediate, normal, rapid and ultra‑rapid metabolisers. Three metabolites have been detected in human plasma. The exposure of the most abundant metabolite MYK‑1078 in human plasma was less than 4% of the exposure of mavacamten, and the other two metabolites had exposures less than 3% of the exposure of mavacamten indicating these would have minimal to no impact on the overall activity of mavacamten. In CYP2C19 poor metabolisers mavacamten is metabolised primarily by CYP3A4. No data are available on the metabolite profile in CYP2C19 poor metabolisers.

Effect of mavacamten on other CYP enzymes

Based on pre-clinical data, for a dose up to 5 mg in CYP2C19 poor metabolisers and for a dose up to 15 mg in CYP2C19 intermediate to ultra‑rapid metabolisers, mavacamten is not an inhibitor of CYP 1A2, 2B6, 2C8, 2D6, 2C9, 2C19, or 3A4 at clinically relevant concentrations.

Effect of mavacamten on transporters

In vitro data indicate that mavacamten is not an inhibitor of major efflux transporters (P‑gp, BCRP, BSEP, MATE1, or MATE2‑K) or major uptake transporters (organic anion transporting polypeptides [OATPs], organic cation transporters [OCTs], or organic anion transporters [OATs]) at therapeutic concentrations for a dose up to 5 mg in CYP2C19 poor metabolisers and for a dose up to 15 mg in CYP2C19 intermediate to ultra‑rapid metabolisers.

Elimination

Mavacamten is cleared from plasma primarily by metabolism through cytochrome P450 enzymes. Terminal half-life is 6 to 9 days in CYP2C19 normal metabolisers and 23 days for CYP2C19 poor metabolisers.

Half‑life is estimated to be, 6 days for CYP2C19 ultra‑rapid metabolisers, 8 days for CYP2C19 rapid metabolisers, and 10 days for CYP2C19 intermediate metabolisers.

Drug accumulation occurs with an accumulation ratio about 2‑fold for C_max and about 7‑fold for AUC in CYP2C19 normal metabolisers. The accumulation depends on the metabolism status for CYP2C19 with the largest accumulation observed in CYP2C19 poor metabolisers. At steady‑state, the peak‑to‑trough plasma concentration ratio with once daily dosing is approximately 1.5.

Following a single 25 mg dose of ¹⁴C labelled mavacamten in CYP2C19 normal metabolisers, 7% and 85% of the total radioactivity was recovered in the faeces and urine of CYP2C19 normal metabolisers, respectively. Unchanged active substance accounted for approximately 1% and 3% of the administered dose in the faeces and urine, respectively.

CYP2C19 phenotype

Polymorphic CYP2C19 is the main enzyme involved in the metabolism of mavacamten. An individual carrying two normal function alleles is a CYP2C19 normal metaboliser (e.g., *1/*1). An individual carrying two non‑functional alleles is a CYP2C19 poor metaboliser (e.g., *2/*2, *2/*3, *3/*3).

The incidence of CYP2C19 poor metaboliser phenotype ranges from approximately 2% in Caucasian to 18% in Asian populations.

Linearity/non-linearity

Exposure to mavacamten increased approximately dose proportionally between 2 mg and 48 mg and is expected to result in dose proportional exposure increase across the therapeutic range of 2.5 mg to 5 mg in CYP2C19 poor metabolisers and 2.5 mg to 15 mg in CYP2C19 intermediate to ultra‑rapid metabolisers.

Special populations

No clinically significant differences in the PK of mavacamten were observed using population PK modelling based on age, sex, race or ethnicity.

Hepatic impairment

A single dose PK study was conducted in patients with mild (Child-Pugh class A) or moderate (Child‑Pugh class B) hepatic impairment, as well as a control group with normal hepatic function. Mavacamten exposures (AUC) increased 3.2‑fold and 1.8‑fold in patients with mild and moderate impairment, respectively, compared to patients with normal hepatic function. There was no effect of hepatic function on C_max, consistent with no change in the rate of absorption and/or volume of distribution. The amount of mavacamten excreted in urine in all 3 studied groups was 3%. A dedicated PK study has not been conducted in patients with severe (Child-Pugh class C) hepatic impairment.

Renal impairment

Approximately 3% of a mavacamten dose is excreted in the urine as parent substance. A population PK analysis, which comprised eGFR down to 29.5 mL/min/1.73m², demonstrated no correlation between renal function and exposure. A dedicated PK study has not been conducted in patients with severe renal impairment (eGFR < 30 mL/min/1.73m²).

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. Toxicology findings were generally related to adverse reductions on cardiac function consistent with exaggerated primary pharmacology in healthy animals. These effects occurred at clinically relevant exposures.

Reproductive toxicity and fertility

In reproductive toxicity studies, there was no evidence of effects of mavacamten on mating and fertility in male or female rats or in the viability and fertility of offspring of dams at any dose tested. However, plasma exposures (AUC) of mavacamten at the highest doses tested were less than in humans at the maximum recommended human dose (MRHD).

Embryo-foetal and postnatal development

Mavacamten adversely affected embryo-foetal development in rats and rabbits. When mavacamten was administered orally to pregnant rats during the period of organogenesis, decreased mean foetal body weight, increases in post implantation loss, and foetal malformations (visceral and skeletal) were observed at clinically relevant exposures. Visceral malformations involved heart malformation in foetuses, including one total situs inversus, while skeletal malformations were manifested mostly as increased incidences of fused sternebrae.

When mavacamten was administered orally to pregnant rabbits during the period of organogenesis, visceral and skeletal malformations were noted, consisting of malformations of the great vessels (dilatation of pulmonary trunk and/or aortic arch), cleft palate and higher incidences of fused sternebrae. Maternal plasma exposure levels (AUC) at the no effect dose level for embryo-foetal development in both species were less than those in humans at the MRHD.

In a pre- and post-natal development study, administration of mavacamten to pregnant rats from gestation day 6 to lactation/post-partum day 20 did not result in adverse effects in the dams or offspring exposed daily from before birth (in utero) through lactation. The maternal exposure was less than the MRHD. No information is available on the excretion of mavacamten in animal milk.

Capsule content

Silica, colloidal hydrated

Mannitol (E421)

Hypromellose (E464)

Croscarmellose sodium (E468)

Magnesium stearate

Capsule shell

All strengths

Gelatin

Titanium dioxide (E171)

CAMZYOS 2.5 mg hard capsules

Iron oxide black (E172)

Iron oxide red (E172)

CAMZYOS 5 mg hard capsules

Iron oxide yellow (E172)

CAMZYOS 10 mg hard capsules

Iron oxide red (E172)

CAMZYOS 15 mg hard capsules

Iron oxide black (E172)

Printing ink

Iron oxide black (E172)

Shellac (E904)

Propylene glycol (E1520)

Ammonia solution, concentrated (E527)

Potassium hydroxide (E525)

Not applicable.

Store at or below 30°C.

Polyvinylchloride (PVC) / Polychlorotrifluoroethylene (PCTFE) / Aluminium foil blister containing 14 hard capsules.

Pack size of 14 or 28 hard capsules.

Not all pack sizes may be marketed.

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