Chemical formula: C₁₈H₁₉N₅O₂ Molecular mass: 337.154 g/mol PubChem compound: 139331495
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 hypertrophic cardiomyopathy (HCM). The consequent reduction in cardiac contractility reduces left ventricular outflow tract (LVOT) obstruction in HCM patients.
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.
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.
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.
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.
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.
Aficamten is rapidly absorbed with a median time to maximum concentration (tmax) of 1.5 to 2 hours. Aficamten maximum concentration (Cmax) and trough concentration (Ctrough) 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 Cmax were observed following its administration with a high-fat, high-calorie meal.
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.
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.
Aficamten has a median terminal half-life (t½) 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 t½ 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.
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).
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.
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.
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.
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.
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