Abstract
Obstructive hypertrophic cardiomyopathy (oHCM) is a subtype of HCM characterized by left ventricular outflow tract obstruction resulting from cardiac muscle hypertrophy and anatomic alterations in the mitral valve and apparatus. Mavacamten, a cardiac myosin inhibitor metabolized primarily by CYP2C19 in the liver, is the first and only targeted medication approved for the treatment of symptomatic New York Heart Association (NYHA) class II–III oHCM. Previous pharmacokinetic (PK) results of mavacamten in healthy Caucasian, Japanese, and Asian participants demonstrated that mavacamten exposure was affected by CYP2C19 metabolism status. This open‐label, parallel‐group, phase I trial aimed to determine the PK and safety of mavacamten in healthy Chinese participants with different CYP2C19 genotypes. The primary outcome was to define the PK of mavacamten in healthy Chinese participants; the secondary outcome was to examine safety and tolerability. After a single oral dose of 15 or 25 mg mavacamten in fasted healthy adult Chinese individuals, C max was reached within a median T max of 0.6–1.5 h, indicating rapid absorption. Inter‐individual variability was moderate, and individuals carrying non‐functional CYP2C19 alleles (*2/*2, *3/*3, or *2/*3) exhibited longer half‐life and increased total exposure. After stratification of CYP2C19 genotypes, total mavacamten exposures were similar among different ethnic groups when compared with prior PK studies. No significant adverse events were observed in this study. Single oral administration of mavacamten at 15 mg was well tolerated across all CYP2C19 genotypes, and 25 mg dose was well tolerated in healthy participants with CYP2C19 genotypes UM/RM/NM. The PK profile of mavacamten in the healthy Chinese population was consistent with that in other healthy populations.
Study Highlights.
WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
Mavacamten, a first‐in‐class cardiac myosin inhibitor, has been approved for the treatment of obstructive hypertrophic cardiomyopathy (oHCM) in 5 continents. This approval marks a significant breakthrough in oHCM treatment, as it provides a targeted approach to addressing the underlying mechanisms of oHCM. Prior studies conducted in Caucasian, Japanese, and Asian populations suggested that CYP2C19 genotype might influence mavacamten exposure.
WHAT QUESTION DID THIS STUDY ADDRESS?
This bridging study assessed the pharmacokinetics and safety of mavacamten in healthy adult Chinese participants with different genotypes of CYP2C19.
WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
The pharmacokinetic profile of mavacamten in the Chinese population was found to be consistent with previous research, featuring rapid absorption and moderate inter‐individual variability. The total exposure of mavacamten varied based on the individual's CYP2C19 genotypes, with participants classified as poor metabolizers showing higher exposure and longer half‐life. Mavacamten was generally well tolerated, with no observed risk of cardiac toxicity in this study. No significant safety concerns emerged among participants classified as intermediate or poor metabolizers of CYP2C19.
HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?
This is the first study that provides the pharmacokinetic and safety profile of mavacamten in the Chinese population. These findings support an ongoing phase III trial of mavacamten in Chinese patients with oHCM.
INTRODUCTION
Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder defined by left ventricular (LV) hypertrophy that cannot be explained by another cardiac or systemic disease. It is a chronic and often progressive disease of the cardiomyocyte. Two HCM phenotypes are recognized based on the presence or absence of obstruction of the left ventricular outflow tract (LVOT): obstructive HCM (oHCM) and non‐obstructive HCM. The disease often has a genetic basis and the pathophysiology is complex and not yet fully understood. 1 , 2 , 3 In patients with HCM, the myocardium becomes hypertrophied leading to cardiac dysfunction, resulting in significant comorbidities including heart failure, arrhythmia, and rarely, sudden death. 2 In oHCM, thickening of the heart muscle and anatomic alterations in the mitral valve and apparatus lead to LVOT obstruction, 4 which can cause symptoms such as shortness of breath, chest pain, and fainting, particularly during exercise. 5
Treatment for HCM depends on the severity of the disease and the presence of symptoms. In oHCM, medications such as beta‐blockers, calcium channel blockers, and disopyramide are used to relieve symptoms and improve blood flow, although they only have limited effectiveness and none of them have been specifically approved for the treatment of oHCM. In severe cases with LVOT gradient ≥50 mmHg, alcohol septal ablation and surgical septal myectomy may be needed to remove part of the thickened heart muscle. There is an increased risk of dysrhythmia, and a pacemaker or defibrillator may need to be implanted to regulate the heart's rhythm. 4 , 5 , 6
Mavacamten—a cardiac myosin inhibitor—is the first and only medication approved by the United States Food and Drug Administration, in 2022, for the treatment of adults with symptomatic New York Heart Association class II–III oHCM to improve functional capacity and symptoms. 7 The mechanism of action of mavacamten involves targeting the underlying pathophysiology of oHCM by reducing the number and activity of actin‐myosin bridges and alleviating hypercontractility. Mavacamten works by inhibiting the activity of the protein myosin, which is responsible for the contraction of heart muscle cells, and consequently helps to relax the heart muscle and improves diastolic function. 5 , 7 , 8 In prior phase III clinical studies, mavacamten significantly improved exercise capacity and LVOT obstruction, reduced important biomarkers of cardiac strain compared with placebo in patients with symptomatic oHCM, and also demonstrated a favorable safety profile. 9 , 10 , 11 The results of the phase III VALOR‐HCM trial (NCT04349072) demonstrated a statistically significant and clinically meaningful reduction for the primary end point, the composite of proceeding to septal reduction therapy (SRT) or remaining SRT Guideline–eligible after 16 weeks of treatment with mavacamten compared with placebo, among patients with symptomatic oHCM who met the 2011 American College of Cardiology Foundation/American Heart Association Guideline referral criteria for SRT. 12
Previous pharmacokinetic (PK) studies of mavacamten have provided important information about its absorption, distribution, metabolism, and elimination in humans. Mavacamten is rapidly absorbed following oral administration with peak plasma concentrations reached in around 1 h. The bioavailability of mavacamten is at least 85%, and it exhibits dose‐proportional PKs over the clinically relevant dose range of 1–15 mg. Mavacamten is extensively metabolized in the liver, primarily through CYP2C19 (74%), CYP3A4 (18%), and CYP2C9 (8%), and it is mainly excreted in urine (3% unchanged). 7 , 13 There is evidence indicating that the CYP2C19 genotype may influence mavacamten exposure. Normal metabolizers carry two functional alleles of CYP2C19, and poor metabolizers have two non‐functional alleles. 7 Higher plasma concentrations and longer half‐lives of mavacamten were observed in individuals who were poor metabolizers (PM) of CYP2C19 compared with normal metabolizers (NM). 7 , 13 This suggests that CYP2C19 genotyping may be helpful in dosing mavacamten. The prevalence of CYP2C19 PM varies depending on ancestry and is approximately 2% in Europeans, 4% in African Americans, and 14% in Chinese. 14
Currently, clinical studies of mavacamten in healthy participants and patients with oHCM have been conducted in the United States, the European Union, the United Kingdom, Australia, and Japan. The current bridging study (LB2001‐101) was designed to determine the PK and safety of mavacamten in healthy adult Chinese participants with different genotypes of CYP2C19.
METHODS
Study design and participants
This open‐label, parallel‐group, phase I trial (LB2001‐101) was conducted at a single center in China. Eligible patients were healthy Chinese adults (aged 18–60 years) who were CYP2C19 ultra‐rapid metabolizers (UM; *17/*17), CYP2C19 rapid metabolizers (RM; *1/*17), CYP2C19 NM (*1/*1), CYP2C19 intermediate metabolizers (IM; *1/*2 or *1/*3), or CYP2C19 PM (*2/*2, *3/*3, or *2/*3) as per central laboratory phenotype determination. Participants had a body mass index (BMI) of ≥18 and ≤30 kg/m2 and a resting left ventricular ejection fraction (LVEF) ≥55% by echocardiography. Before dosing, each participant had no clinically significant abnormalities in their medical history, physical examinations, vital signs, clinical laboratory tests, or 12‐lead electrocardiograms (ECGs).
Key exclusion criteria included as follows: history of clinically significant arrhythmia, LV systolic dysfunction, or coronary artery disease; ECG showing corrected QT interval (QTc) >450 ms; positive results for human immunodeficiency virus test, hepatitis B virus, or hepatitis C virus; hypersensitivity to mavacamten or any of the components of its formulation; any known clinically significant abnormalities, conditions, or diseases that would pose a risk to participant's safety or interfere with study evaluation, procedures, or its completion. Details of the inclusion and exclusion criteria are provided in the Supplementary Information, and inclusion and exclusion criteria.
All prescribed medication was prohibited from 28 days before screening through the end of study, and all over‐the‐counter medication (including herbal preparations and nutritional supplements, but not including up to 1.5 g acetaminophen daily) was prohibited from 14 days before screening through the end of study.
The study was performed in accordance with the principles of the Declaration of Helsinki, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Guideline for Good Clinical Practice, and local applicable regulatory requirements for clinical studies. All participants provided written informed consent. The study protocol, amendments, and informed consent were approved by the institutional review board/ethics committee at the study center. The trial is registered at ClinicalTrials.gov, number: NCT05135871.
End points
The primary objective was to characterize PK after a single, fasted, oral dose of mavacamten in healthy adult Chinese participants with different CYP2C19 genotypes. End points included area under the concentration–time curve from time zero to the last quantifiable concentration (AUC0−last), area under the concentration–time curve from time zero extrapolated to infinity (AUC0−inf), maximum concentration (C max), time to maximum concentration (T max), apparent terminal elimination half‐life (T ½), apparent volume of distribution (V d /F), and apparent clearance (CL/F). Secondary objectives were safety and tolerability, which were assessed via adverse events (AEs), vital signs, physical examination findings, ECG parameters, and clinical laboratory tests.
Procedures
CYP2C19 genotypes were analyzed by the Beijing Prohealth Clinical Laboratory Co., Ltd (Beijing, China) using the ABI 7500 Real‐Time PCR System. Participants were divided into four cohorts according to CYP2C19 genotype (Cohort 1: CYP2C19 UM/RM/NM, 15 mg mavacamten; Cohort 2: CYP2C19 UM/RM/NM, 25 mg mavacamten; Cohort 3: CYP2C19 IM, 15 mg mavacamten; and Cohort 4: CYP2C19 PM, 15 mg mavacamten). For participants with CYP2C19 UM/RM/NM, enrollment in Cohort 1 was followed by Cohort 2. Participants could be enrolled in Cohort 3 and Cohort 4 in parallel with Cohort 1. The study period for each participant was up to 16 weeks (Figure S1).
A single oral dose of mavacamten under fasted conditions was administered to each participant to evaluate the PK profile. Participants in Cohorts 1, 3, and 4 received 15 mg mavacamten, and participants in Cohort 2 received 25 mg mavacamten. Dose selection was based on findings from previous clinical or PK studies of mavacamten. To bridge PK data in the Chinese population with prior clinical or PK mavacamten studies, participants with CYP2C19 genotypes of UM/NM/RM received a single fasted dose of 25 mg mavacamten (Cohort 2), the same dose received by healthy Japanese and Caucasian participants with CYP2C19 UM/NM/RM; participants with CYP2C19 genotypes of IM or PM received a single fasted dose of 15 mg mavacamten (Cohorts 3 and 4, respectively), the same dose received by healthy Japanese participants with CYP2C19 IM and healthy Asian participants with CYP2C19 PM. 13 To evaluate the PK profiles of mavacamten in Chinese participants with different genotypes and make an ethnic comparison with PK findings for other populations, Cohorts 1, 3, and 4 received the same dose of 15 mg mavacamten.
PK assessments
Blood samples (3 mL whole blood) were collected at each timepoint for PK analysis, stored at the study site at −20°C to −90°C, and shipped to a central laboratory for drug concentration analysis. The PK parameters of mavacamten were assessed pre‐dose (within 60 min before dosing), 10, 20, 30, 45 min, 1, 1.5, 2, 3, 4, 8, 12, 24 and 48 h post‐dose. Additional blood samples were also collected at Days 7, 10, 14, 21, 28, 35, 45, 60, and 75 (±1 day). The determination of mavacamten plasma concentrations was performed by Q Squared Solutions Co., Ltd (Beijing, China), using validated liquid chromatography with the tandem mass spectrometry method. The lower limit of quantification was set at 0.2 ng/mL, and the upper limit of quantification was 200 ng/mL. Calibration standards were prepared fresh for each analytical batch and used to generate a weighted (1/x 2) linear regression calibration curve with a dynamic range of 0.200–200 ng/mL. Quality control performance (accuracy and precision) was within ±15% (±20.0% at LLOQ) at four concentrations (0.2, 0.6, 75, and 150 ng/mL) across method qualification and sample analysis batches. A LC/MS/MS method for the quantitation of mavacamten in 50.0 μL of K2EDTA human plasma has been validated over the concentration range of 0.200–200 ng/mL. The validity of preparing samples using a 20‐fold dilution factor was demonstrated. All stability experiments conducted during this validation showed no indication of instability.
Safety assessment
AEs, vital signs, laboratory tests, and ECGs were recorded throughout the trial. AEs were coded according to the Medical Dictionary for Regulatory Activities Terminology version 24.1 and graded per the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.
Sample size estimation
Approximately 8 to 12 participants in each cohort were expected to provide sufficient data to allow the assessment of the safety, tolerability, and PK profile of mavacamten in Chinese participants based on Chinese regulatory considerations.
Statistical analysis
The PK analysis set included all participants exposed to mavacamten with at least one plasma concentration result and no serious protocol violations affecting PK parameter results. The safety analysis set included all participants exposed to mavacamten, regardless of dose. The safety analysis period was defined as the time between study drug administration and the end‐of‐study visit.
The mean (± standard deviation [SD]) concentration–time curve was plotted for each cohort. The PK parameter data were listed and summarized descriptively. To examine the exposure to mavacamten for participants with the UM/RM/NM versus IM versus PM genotype, an analysis of variance model was constructed using log‐transformed AUC0−last, AUC0−inf, and C max. The dependent variable was the ln‐transformed primary PK parameters (AUC0−last, AUC0−inf, and C max), with the cohort as independent variable. The AUC0−last, AUC0−inf, and C max were compared between Cohort 1 and Cohort 2 (CYP2C19 UM/RM/NM), Cohort 3 (CYP2C19 IM), and Cohort 4 (CYP2C19 PM), respectively. The geometric mean ratio between cohorts and 90% confidence intervals were calculated for each parameter (with Cohort 1 as the reference group for data analysis).
The PK parameters were calculated using a non‐compartmental model by WinNonlin version 8.3.4. Other statistical analyses were performed using SAS statistical software version 9.4.
RESULTS
Demographics
A total of 45 healthy Chinese participants were enrolled and assigned to four cohorts according to CYP2C19 genotype: Cohort 1 (12 participants), Cohort 2 (13 participants), Cohort 3 (12 participants), and Cohort 4 (eight participants).
A total of 44 participants received the study drug and completed the study. One participant in Cohort 2 withdrew from the study prior to the administration of the study drug due to an abnormal ECG and was excluded from the PK analysis set and safety analysis set. One additional participant was enrolled in Cohort 2 due to the withdrawal of the aforementioned participant, resulting in a total of 13 participants enrolled in Cohort 2. One participant in Cohort 3 was excluded from the PK analysis set due to a major protocol deviation of using the prohibited moderate CYP2C19 inhibitor omeprazole, which has the potential to affect the PK parameters. As a result, 44 participants were included in the safety analysis (Cohort 1, n = 12; Cohort 2, n = 12; Cohort 3, n = 12; Cohort 4, n = 8); 43 participants were included in the PK analysis (Cohort 1, n = 12; Cohort 2, n = 12; Cohort 3, n = 11; Cohort 4, n = 8).
The participants had a median age of 30 years, a median BMI of 23.8 kg/m2, and a median LVEF of 67.5% (Table 1). Most participants (n = 33, 75%) were male. For Cohorts 1 and 2, one (8.3%) participant had CYP2C19 RM (*1/*17) genotype and 11 (91.7%) had CYP2C19 NM (*1/*1) genotype in each cohort. For Cohort 3, 10 (83.3%) participants had CYP2C19 IM (*1/*2) genotype and two (16.7%) had CYP2C19 IM (*1/*3) genotype. For Cohort 4, six (75.0%) participants had CYP2C19 PM (*2/*2) genotype and two (25.0%) had CYP2C19 PM (*2/*3) genotype.
TABLE 1.
Participant demographics and baseline characteristics (safety analysis set).
| Cohort 1 (N = 12) | Cohort 2 (N = 12) | Cohort 3 (N = 12) | Cohort 4 (N = 8) | Total (N = 44) | |
|---|---|---|---|---|---|
| Median age, years (range) | 26.0 (20–35) | 28.5 (21–45) | 30.5 (19–42) | 35.0 (30–43) | 30.0 (19–45) |
| Gender, n (%) | |||||
| Male | 9 (75.0) | 9 (75.0) | 9 (75.0) | 6 (75.0) | 33 (75.0) |
| Female | 3 (25.0) | 3 (25.0) | 3 (25.0) | 2 (25.0) | 11 (25.0) |
| Median body mass index a , kg/m2 (range) | 24.6 (20.9–28.4) | 24.4 (19.5–27.0) | 22.8 (20.7–27.4) | 22.3 (20.3–26.8) | 23.8 (19.5–28.4) |
| CYP2C19 genotype, n (%) | |||||
| UM | |||||
| *17/*17 | 0 | 0 | 0 | 0 | 0 |
| RM | |||||
| *1/*17 | 1 (8.3) | 1 (8.3) | 0 | 0 | 2 (4.5) |
| NM | |||||
| *1/*1 | 11 (91.7) | 11 (91.7) | 0 | 0 | 22 (50.0) |
| IM | |||||
| *1/*2 | 0 | 0 | 10 (83.3) | 0 | 10 (22.7) |
| *1/*3 | 0 | 0 | 2 (16.7) | 0 | 2 (4.5) |
| PM | |||||
| *2/*2 | 0 | 0 | 0 | 6 (75.0) | 6 (13.6) |
| *3/*3 | 0 | 0 | 0 | 0 | 0 |
| *2/*3 | 0 | 0 | 0 | 2 (25.0) | 2 (4.5) |
| Median LVEF, % (range) | 69.5 (61–74) | 66.5 (61–74) | 66.5 (61–72) | 66.0 (55–69) | 67.5 (55–74) |
Abbreviations: CYP, cytochrome P450; IM, intermediate metabolizer; LVEF, left ventricular ejection fraction; NM, normal metabolizer; PM, poor metabolizer; RM, rapid metabolizer; UM, ultra‐rapid metabolizer.
Body mass index = weight (kg)/[height (cm)/100]2(kg/m2).
PK analysis
The mean plasma concentration–time curves of each cohort following a single oral dose of mavacamten are shown in Figure 1.
FIGURE 1.
Mean (±SD) mavacamten plasma concentration–time data through 24 h (a) and 0–1776 h (b) per cohort in linear scale and semi‐logarithmic scale. Mavacamten was rapidly absorbed after a single oral dose. Datapoints represent mean ± standard deviation. Cohort 1: CYP2C19 UM/RM/NM, 15 mg mavacamten; Cohort 2: CYP2C19 UM/RM/NM, 25 mg mavacamten; Cohort 3: CYP2C19 IM, 15 mg mavacamten; Cohort 4: CYP2C19 PM, 15 mg mavacamten. CYP, cytochrome P450; IM, intermediate metabolizer; NM, normal metabolizer; PM, poor metabolizer; RM, rapid metabolizer; UM, ultra‐rapid metabolizer.
After a single oral dose of mavacamten in fasted healthy adult Chinese individuals, the C max was reached within a median T max of 0.6–1.5 h, indicating rapid absorption. The inter‐individual variability was moderate, as the ranges of geometric coefficient of variation (CV%) for C max, AUC0−last, AUC0−inf, and T ½ were 25.7–40.0%, 21.1–50.5%, 21.2–52.5%, and 22.3–42.3%, respectively. The PK profiles of mavacamten varied among different cohorts, with a geometric mean T ½ of 120.3, 143.6, 205.4, and 572.0 h; geometric mean AUC0−last of 9956, 20,040, 18,270, and 39,980 h*ng/mL; and geometric mean AUC0−inf of 10,030, 20,280, 18,430, and 45,810 h*ng/mL for Cohorts 1 to 4, respectively. Individuals carrying non‐functional CYP2C19 alleles exhibited longer half‐life and increased total exposure (Table 2).
TABLE 2.
PK parameters of mavacamten following a single oral administration of mavacamten (PK analysis set).
| Cohort 1 UM/RM/NM 15 mg (N = 12) | Cohort 2 UM/RM/NM 25 mg (N = 12) | Cohort 3 IM 15 mg (N = 11) | Cohort 4 PM 15 mg (N = 8) | |
|---|---|---|---|---|
| C max (μg/mL), geometric mean (CV%) | 395.4 (40.0) | 571.8 (25.7) | 485.2 (35.0) | 435.7 (35.7) |
| T max (h), median (range) | 0.9 (0.5–3.0) | 1.5 (0.5–4.0) | 0.8 (0.5–3.0) | 0.6 (0.3–1.0) |
| T ½ (h), geometric mean (CV%) | 120.3 (23.4) | 143.6 (42.3) | 205.4 (22.3) | 572.0 (25.0) |
| AUC0−last (h*ng/mL), geometric mean (CV%) | 9956 (35.6) | 20,040 (50.5) | 18,270 (21.1) | 39,980 (23.6) |
| AUC0−inf (h*ng/mL), geometric mean (CV%) | 10,030 (35.4) | 20,280 (52.5) | 18,430 (21.2) | 45,810 (25.5) |
| %AUCex, geometric mean (CV%) | 0.7 (44.9) | 0.7 (112.2) | 0.8 (25.9) | 11.2 (53.6) |
| CL/F (mL/h), geometric mean (CV%) | 1495.0 (35.4) | 1233.0 (52.5) | 814.0 (21.2) | 327.5 (25.5) |
| V d /F (mL), geometric mean (CV%) | 259,500 (29.9) | 255,300 (16.6) | 241,200 (23.1) | 270,200 (27.0) |
Abbreviations: %AUCex, percentage of extrapolation of AUC0−inf from t last; AUC0−inf, area under the concentration–time curve from time zero extrapolated to infinity; AUC0−last, area under the concentration–time curve from time zero to the last quantifiable concentration; CL/F, apparent clearance; C max, maximum concentration; CV, coefficient of variation; IM, intermediate metabolizer; N, number of participants in the analysis population; NM, normal metabolizer; PK, pharmacokinetics; PM, poor metabolizer; RM, rapid metabolizer; T ½, apparent terminal elimination half‐life; t last, time of last measurable concentration; T max, time to maximum concentration; UM, ultra‐rapid metabolizer; V d /F, apparent volume of distribution.
Table 3 shows the comparison of PK parameters of mavacamten between cohorts. The geometric mean ratio showed that total exposure in the IM group (Cohort 3) was approximately 1.8‐fold of that in the UM/RM/NM group (Cohort 1); total exposure in the PM group (Cohort 4) was approximately fourfold of that in the UM/RM/NM group. In the UM/RM/NM groups, total exposure of Cohort 2 (25 mg mavacamten) was around twofold of that in Cohort 1 (15 mg mavacamten). Increased exposure in the PM group versus the UM/RM/NM group is supported by the box plots of dose‐normalized C max, AUC0−last, and AUC0−inf (Figure 2). Among individuals with the same CYP2C19 genotypes (UM/RM/NM), mavacamten exposure normalized by dose was comparable between groups regarding C max, AUC0−last, and AUC0−inf after administering 25 mg and 15 mg doses (Cohort 2 and Cohort 1) (Figure 2).
TABLE 3.
Comparison of PK parameters of mavacamten between cohorts (PK analysis set).
| Compared cohort | C max (μg/mL), geometric mean ratio (95% CI) | AUC0−last (h*ng/mL), geometric mean ratio (95% CI) | AUC0−inf (h*ng/mL), geometric mean ratio (95% CI) |
|---|---|---|---|
| Cohort 2/Cohort 1 | 1.446 (1.15, 1.82) | 2.013 (1.59, 2.55) | 2.021 (1.59, 2.58) |
| Cohort 3/Cohort 1 | 1.227 (0.97, 1.55) | 1.835 (1.44, 2.34) | 1.837 (1.43, 2.35) |
| Cohort 4/Cohort 1 | 1.102 (0.85, 1.42) | 4.016 (3.08, 5.23) | 4.566 (3.48, 5.99) |
Abbreviations: AUC0−inf, area under the concentration–time curve from time zero extrapolated to infinity; AUC0−last, area under the concentration–time curve from time zero to the last quantifiable concentration; C max, maximum concentration; PK, pharmacokinetics.
FIGURE 2.
Box plots of dose‐normalized C max (a), AUC0−last (b), and AUC0−inf (c) of mavacamten (PK analysis set). Total exposures of mavacamten in the IM group (Cohort 3) and the PM group (Cohort 4) were higher than those in the UM/RM/NM groups (Cohorts 1 and 2). Datapoints represent minimum, first quartile, median, third quartile, and maximum. AUC0−inf, area under the concentration–time curve from time zero extrapolated to infinity; AUC0−last, area under the concentration–time curve from time zero to the last quantifiable concentration; C max, maximum concentration; IM, intermediate metabolizer; NM, normal metabolizer; PK, pharmacokinetics; PM, poor metabolizer; RM, rapid metabolizer; UM, ultra‐rapid metabolizer.
There was one outlier in Cohort 2 who met all the inclusion criteria and none of the exclusion criteria, with AUC parameters 3.8 to 6.4 times higher than other participants in the same cohort. After removing the outlier in Cohort 2, the geometric mean of inter‐individual C max, AUC0−last, and AUC0−inf was 559.0 (CV%: 25.6%) ng/mL, 17,570 (CV%: 14.6%) h*ng/mL, and 17,690 (CV%: 14.5%) h*ng/mL, respectively. The geometric mean was 128.6 (CV%: 15.1%) h for T½, 1413 (CV%: 14.5%) mL/h for CL/F, and 262,300 (CV%: 14.3%) mL for V d /F. The PK parameters of mavacamten in Cohort 2 with or without the outlier are presented in Table S1. Comparing Cohort 2 without the outlier with Cohort 1, the geometric mean ratio of C max was approximately 1.4‐fold, and for AUC0−last and AUC0−inf, approximately 1.8‐fold (Table S2).
Safety
The overview of treatment‐emergent AEs (TEAEs) is listed in Table 4 and Table S3. A total of 21 (47.7%) participants experienced at least one TEAE during the study. Only one participant in Cohort 3 reported one moderate TEAE (abdominal pain), while all other reported TEAEs were mild in severity. The one moderate TEAE was considered not related to the study drug. The most frequent TEAEs were upper respiratory tract infection (20.5%), blood fibrinogen increased (6.8%), and chest pain (6.8%). One participant from Cohort 2 (chest pain) and one participant from Cohort 4 (hemoglobin decreased) each had a single mild TEAE related to the study drug, whereas the TEAEs reported by the remaining participants were assessed as not related to the study drug.
TABLE 4.
Overview of TEAEs (safety analysis set).
| n (%) | Cohort 1 (N = 12) | Cohort 2 (N = 12) | Cohort 3 (N = 12) | Cohort 4 (N = 8) | Total (N = 44) |
|---|---|---|---|---|---|
| TEAEs | 3 (25.0) | 6 (50.0) | 9 (75.0) | 3 (37.5) | 21 (47.7) |
| Worst severity of TEAE | |||||
| Mild | 3 (25.0) | 6 (50.0) | 8 (66.7) | 3 (37.5) | 20 (45.5) |
| Moderate | 0 | 0 | 1 (8.3) | 0 | 1 (2.3) |
| Severe | 0 | 0 | 0 | 0 | 0 |
| TEAEs related to the study drug | 0 | 1 (8.3) | 0 | 1 (12.5) | 2 (4.5) |
| Serious TEAEs | 0 | 0 | 0 | 0 | 0 |
| TEAEs leading to treatment discontinuation | 0 | 0 | 0 | 0 | 0 |
| TEAEs leading to death | 0 | 0 | 0 | 0 | 0 |
| AESI | 0 | 0 | 0 | 0 | 0 |
| TEAEs occurred in ≥2 participants of total | |||||
| Upper respiratory tract infection | 2 (16.7) | 3 (25.0) | 3 (25.0) | 1 (12.5) | 9 (20.5) |
| Blood fibrinogen increased | 0 | 0 | 2 (16.7) | 1 (12.5) | 3 (6.8) |
| Chest pain | 0 | 2 (16.7) | 1 (8.3) | 0 | 3 (6.8) |
| White blood cell count decreased | 0 | 1 (8.3) | 0 | 1 (12.5) | 2 (4.5) |
| Headache | 0 | 1 (8.3) | 1 (8.3) | 0 | 2 (4.5) |
Note: Life‐threatening and fatal events were classified as severe in severity.
Abbreviations: AESI, adverse event of special interest; N, number of participants in the analysis population; n, number of participants with at least one event in the specified category, percentage is calculated with N as the denominator; TEAE, treatment‐emergent adverse event.
TEAEs related to the potential risk of mavacamten, symptomatic LVEF <50%, were not observed in this study. No serious TEAEs or AEs of special interest (including symptomatic overdose, and LVEF ≤30%) were reported in this study. No significant trends of shifts from baseline and no notable differences among the cohorts in terms of laboratory parameters, ECGs, vital signs, and physical examination results were observed.
DISCUSSION
This study investigated the PK of single‐dose mavacamten in healthy adult Chinese participants with different phenotypes of CYP2C19, UM/RM/NM, IM, and PM. The results indicated rapid absorption after a single oral administration of 15 or 25 mg mavacamten, and the inter‐individual variability was moderate. Prolongations of T½ and increased exposure for participants carrying non‐functional CYP2C19 alleles were observed. The total exposures for CYP2C19 IM and CYP2C19 PM were increased approximately 1.8‐ to 4‐fold when compared to CYP2C19 UM/RM/NM. Overall, the PK profile of mavacamten in the Chinese population was consistent with the previously known PK profile of mavacamten in other populations. No apparent difference in PK stratified by ethnicity was observed, once corrected for metabolizer status.
There was an increase in mavacamten exposure between 1056 and 1440 h in a semi‐log scale. This was due to an outlier in Cohort 2, who had the AUC parameters 3.8‐ to 6.4‐fold higher than other participants in the same cohort. In order to assess the impact of the outlier on PK evaluation, an ad hoc analysis was carried out by removing this particular participant from the PK analysis. The outlier in Cohort 2 did not experience TEAEs, took no concomitant medications, and no protocol deviations were recorded during the study. There were no clinically significant abnormalities in the safety tests for this outlier. All the PK parameters were similar with or without the outlier in Cohort 2. The total exposure of mavacamten in participants was approximately 1.4‐ to 1.8‐fold when the dose ratio of mavacamten was 1.67 times (25 mg/15 mg) among CYP2C19 UM/RM/NM genotypes, which was closer to a dose–concentration proportional relationship. The outlier did not significantly affect the conclusions and the titration plan for mavacamten in Chinese patients based on this study. The existence of an outlier showing higher AUC parameters suggested that the PK variability cannot be entirely accounted for by genotype alone. Therefore, an individualized titration scheme based on clinical status and echocardiographic assessment of patient response was adopted for mavacamten. Dose titration starting from 5 mg based on LVEF, and Valsalva LVOT gradient is recommended for mavacamten per the FDA label. 13 While CYP2C19 genotyping for mavacamten initial dose determination is recommended per the EMA label, 15 individualized dosing based on CYP2C19 genotypes to reach the stable dose is not proposed. 16 Genotyping may be a helpful tool; however, it has not been routinely implemented in prospective trials and is not mandated for optimization globally. 13 In addition, no particular safety issues were observed in the IM/PM metabolizers. However, moderate to strong CYP2C19 inhibitors/inducers should be avoided when taking mavacamten.
PK parameters derived from this study (LB2001‐101) were compared with those obtained from prior studies in diverse ethnic populations who received a single dose of mavacamten. Mavacamten was quickly absorbed in this current study and was similar in the studies of healthy Japanese and Caucasian participants (T max: 1.0 h). 13 The PK of once‐daily oral mavacamten in healthy volunteers was approximately dose proportional within a dose range of 1–15 mg, 7 but less than dose proportional between 15 and 25 mg in Japanese participants. In Cohorts 1 and 2 of this study, the results confirmed that the exposure of mavacamten was approximately proportional between 15 and 25 mg mavacamten administered in Chinese participants with CYP2C19 UM/RM/NM. The findings of prolonged clearance and increased exposure in CYP2C19 IM and PM compared with CYP2C19 UM/RM/NM are consistent with results from previous studies. 13 Furthermore, after stratification by CYP2C19 genotype, mavacamten exposures were consistent between Chinese and Caucasians, consistent with the understanding based on previous clinical pharmacological studies of mavacamten. The PK profile for mavacamten was also consistent across various populations/ethnicities once corrected for CYP2C19 phenotype; therefore, dose adjustment based on ethnicity is not warranted.
Single oral administration of mavacamten was found to be safe and well tolerated in healthy participants. There were no serious TEAEs, TEAEs leading to study discontinuation, severe TEAEs, or AEs of special interest observed in this study. The most frequent TEAE was upper respiratory tract infection in the current study, all instances of which were found to be not related to the study drug. Among different CYP2C19 genotypes, there were no notable differences observed and safety results were similar. The risk of heart failure is a black box warning in the United States Prescribing Information for mavacamten. 13 No QT prolongation, symptomatic LVEF <50%, or cardiac failure were observed in the healthy participants in this study. This observation is consistent with prior studies, in which cardiac toxicity was not observed during single dosing. 13 It should be noted that the observation of cardiac adverse effect might be limited due to single dosing in the current study. None of the AEs of special interest, selected based on the phase III EXPLORER‐CN study, 17 were reported in our study. The reduction in LVEF is one safety risk associated with mavacamten, and dose interruption or adjustment is required based on LVEF assessment. 13 In a prior study, an exposure–response model was developed and the simulation suggested that the proportion of patients with LVEF <50% ranged 0.9%–2% at Week 40 across doses from 2.5 to 15 mg. 18 However, LVEF <50% was not observed in this study up to 25 mg. Again, this might be related to the single dosing. Additionally, prior clinical studies of mavacamten showed that the safety and tolerability were similar between mavacamten and placebo. 16 , 19 In our study, though the increase in exposure was fourfold and twofold in participants with CYP2C19 PM and IM, respectively, the incidence of TEAEs was not higher in CYP2C19 PM. Furthermore, only one TEAE each was reported in CYP2C19 UM/RM/NM (25 mg mavacamten) and CYP2C19 PM (15 mg mavacamten). This suggests that AEs do not increase with mavacamten dose, up to 25 mg in healthy participants. Therefore, individualized titration based on clinical status and echocardiographic assessment of patient response is recommended. Overall, single oral administration of mavacamten up to 25 mg in healthy Chinese participants showed a good safety and tolerability profile across all dose groups and genotypes, although the PK analysis showed different exposure levels of mavacamten in different dose groups and different CYP2C19 genotypes.
Mavacamten represents a significant advancement in the treatment of oHCM, offering a targeted approach to addressing the underlying pathophysiology of the disease. It is expected to have a major impact on the management of oHCM, improving oHCM symptoms and decreasing the need for surgical intervention. 1 , 8 , 12 Individual variation of PKs was observed in our study, indicating the importance of individualized titration according to the clinical response and safety monitoring for patients receiving mavacamten. The findings from this study support the individualized dose regimen based on clinical characteristics in a phase III trial that enrolled Chinese patients with symptomatic oHCM (EXPLORER‐CN; NCT05174416), which showed that mavacamten significantly improved Valsalva LVOT obstruction, New York Heart Association functional class, health status, and cardiac structure compared with placebo in these patients, regardless of CYP2C19 phenotype. 16
In conclusion, single‐dose PK of mavacamten in healthy Chinese participants in this study revealed rapid absorption and moderate inter‐individual variability. The total exposure of mavacamten varied depending on CYP2C19 genotypes, with higher exposure in participants with CYP2C19 PM, consistent with the understanding of mavacamten's disposition. Mavacamten was well tolerated overall. No cardiac AEs were observed in this study. No safety signals emerged in participants with CYP2C19 IM or PM. The PK profile of mavacamten in a healthy Chinese population was consistent with that in other healthy populations from prior studies in other ethnicities.
AUTHOR CONTRIBUTIONS
P.H. wrote the manuscript. C.L. and J.Z. designed the study. X.W., N.C., Q.W., Q.W., J.Y., G.C., H.Y., L.W., J.W., Y.J., W.L., J.W., and J.H. performed the study. P.H., J.S., S.M., and W.L. analyzed the data.
FUNDING INFORMATION
This work was supported by the Science and Technology Commission of Shanghai Municipality (22S11904701, 22S11904702), Shanghai LianBio Development Co., Ltd, and Bristol Myers Squibb.
CONFLICT OF INTEREST STATEMENT
P. H. and C. L. are employees of Shanghai LianBio Development Co., Ltd. J. S., Q. W., and M. S. are employees of Bristol Myers Squibb. All other authors declared no competing interests for this work.
Supporting information
Data S1:
ACKNOWLEDGMENTS
We acknowledge funding from the Science and Technology Commission of Shanghai Municipality, and support from Manting Chiang, Shilpa Puli, and Vidya Perera of Bristol Myers Squibb. Vidya Perera was an employee of Bristol Myers Squibb at the time the study was conducted. Medical writing assistance was provided by Jing Yi Lee and Molly Yu from Parexel, which was funded by Shanghai LianBio Development Co., Ltd, and Bristol Myers Squibb.
Wu X, Chen N, Hsu P, et al. Pharmacokinetics and safety of mavacamten in healthy Chinese participants with different CYP2C19 phenotypes. Clin Transl Sci. 2024;17:e13877. doi: 10.1111/cts.13877
Xiaojie Wu and Nanye Chen contributed equally to this study.
A poster based on the present research was presented at the 2024 ASCPT Annual Meeting.
Contributor Information
Cheng Lyu, Email: levvy.lv@aliyun.com.
Jing Zhang, Email: zhangj61@fudan.edu.cn.
DATA AVAILABILITY STATEMENT
The data underlying this article will be shared upon a reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data S1:
Data Availability Statement
The data underlying this article will be shared upon a reasonable request.