Mavacamten

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.

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, simulated steady state exposures are summarized using individualised dosage by phenotype (table).

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.