Abstract
Aim
This first‐in‐human study assessed the safety, tolerability, pharmacokinetics (PK), effect of food on PK and pharmacodynamics of HRS‐1893, a cardiac myosin inhibitor, in healthy subjects.
Methods
In the single ascending dose part, eight subjects in each of the 5‐, 15‐, 50‐, 75‐ and 100‐mg (optional) cohort and 10 subjects in the 30‐mg cohort were randomized in 6:2 and 8:2 ratios, respectively, to receive HRS‐1893 or placebo. Participants from the 30‐mg cohort then entered a food effect study where they received HRS‐1893 or placebo after a high‐fat meal. In the multiple ascending dose part, eight subjects in each of the 10‐, 20‐, 40‐ and 60‐mg (optional) cohorts were randomized (6:2) to receive HRS‐1893 or placebo twice daily for 14 days.
Results
HRS‐1893 was well tolerated within the tested dose range. Following single dosing, the median (5th and 95th percentile) maximum plasma concentration of HRS‐1893 ranged from 343 (241 and 436) to 1090 (990 and 1430) ng/ml and was reached within 1.0‐ to 2.0‐h post‐administration. Drug exposure increased in a less‐than‐dose‐proportional manner with dose escalation. AUC 0−t ranged from 1890 (1710 and 2520) to 10 100 (7710 and 11 600) h·ng/ml, and AUC 0‐∞ ranged from 1960 (1820 and 2660) to 11 900 (9260 and 13 100) h·ng/ml. A steady‐state was attained by Day 8 following continuous administration. Food intake had no obvious effect on the PK profile of HRS‐1893 at 30 mg. HRS‐1893 also resulted in favourable changes in cardiac indicators.
Conclusion
HRS‐1893 demonstrated favourable safety and PK profiles, with potential therapeutic efficacy among healthy subjects.
Clinical trial registration
Keywords: pharmacodynamics, pharmacokinetics, phase 1
What is already known about this subject
Hypertrophic cardiomyopathy is a common heritable cardiac disease characterized by left ventricular hypertrophy.
Conventional treatment options often had suboptimal efficacy accompanied by potential safety risks.
Cardiac myosin inhibitors are a novel drug class for the treatment of hypertrophic cardiomyopathy.
What this study adds
HRS‐1893, a novel cardiac myosin inhibitor, was well tolerated at single doses of 5–75 mg and at multiple doses of 10–40 mg among healthy volunteers.
HRS‐1893 plasma concentration reached a steady state in 8 days with twice daily dosing, allowing for a short dosage adjustment period.
HRS‐1893 demonstrated an acceptable safety profile among healthy volunteers, supporting its further development as a novel treatment option for hypertrophic cardiomyopathy.
1. INTRODUCTION
Hypertrophic cardiomyopathy (HCM) is a common heritable cardiac disease, characterized by left ventricular (LV) hypertrophy in absence of secondary causes. 1 , 2 HCM in adults is diagnosed when imaging reveals a maximal end‐diastolic wall thickness of ≥15 mm at any location within the left ventricle, typically assessed through 2D echocardiography or cardiovascular magnetic resonance. 3 Based on the level of resting and provoked peak left ventricular outflow tract gradient (LVOT‐G), HCM can be classified into obstructive and non‐obstructive HCM. Research indicated that over 40% of HCM cases are attributed to mutations in the MYH7 and MYBPC3 genes, which encode myosin heavy chain and myosin binding protein C, respectively. 4 These mutations subsequently impact various aspect of actin‐myosin cross‐bridge cycling, including calcium sensitivity and adenosine triphosphatase (ATPase) activity, ultimately resulting in myocardial hypercontractility and hypertrophic alterations. 1 , 5
Treatment options of HCM include pharmacotherapies and septal reduction therapies. However, conventional medications for HCM, such as beta blockers, non‐dihydropyridine calcium channel blockers and disopyramide, are not disease‐specific thus have insufficient efficacy. 6 , 7 Invasive surgeries, on the other hand, may increase the risk of arrythmia and septal perforation. 8 , 9 Cardiac myosin inhibitors emerged as a novel drug class for the treatment of HCM. By inhibiting myosin ATPase enzyme, myosin inhibitors reduce actin‐myosin crossbridge formation and normalize cardiac contractility. Consequently, the mechanical environment of sarcomere is improved with better relaxation, increased ventricular chamber size and reduced outflow obstruction. Mavacamten and aficamten are two cardiac myosin inhibitors that are currently available. Mavacamten and Aficamten were approved by the US Food and Drug Administration for the treatment of obstructive HCM. 10 , 11 However, there are concerns regarding potential risks of heart failure associated with its use and numerous limitations related to drug interactions. 12 The dosing regimen also requires complex titration with a 12‐week initiation phase for dose adjustment. 12 Similarly, for aficamten, its effect on left ventricular ejection fraction (LVEF) poses risk for heart failure and therefore requires close safety monitoring and biweekly dose adjustment. 13 , 14 Therefore, there remains a significant unmet clinical need in the treatment of obstructive HCM.
HRS‐1893 is a selective and reversible cardiac myosin inhibitor specifically designed to reduce hypercontractility in HCM by inhibiting the activity of myosin ATPase. Preclinical data indicated that HRS‐1893 was mainly eliminated in its parent form via urine, with the metabolites of HRS‐1893 accounting for less than 2% in both blood and urine. HRS‐1893 also demonstrated a reduction in fractional shortening in murine models, exhibiting favourable safety and tolerability profiles. This first‐in‐human study aimed to evaluate the safety, tolerability, pharmacokinetics (PK), effect of food on PK and pharmacodynamics (PD) of HRS‐1893 in healthy volunteers.
2. METHODS
2.1. Study population
The study recruited healthy male and female volunteers aged 18 to 55 years. Eligible participants were required to have a body mass index ranging from 19 to 28 kg/m2, normal results in physical examinations and laboratory tests and no clinically significant abnormalities observed in the 12‐lead electrocardiogram (ECG) and transthoracic echocardiogram (TTE). The QTc Fridericia (QTcF) interval was required to be ≤450 ms for males and ≤470 ms for females. All subjects needed to demonstrate a LVEF of ≥55%. Key exclusion criteria included allergy to any component of the study medication; history of sustained tachyarrhythmia, heart failure, myocardial infarction, angina pectoris, atrioventricular conduction block, torsades de pointes or ventricular tachycardia; clinically significant T‐wave changes; family history of cardiomyopathy, unexplained heart failure, long QT syndrome or Brugada syndrome; abnormal serum potassium, serum calcium or magnesium levels within 6 months prior to screening; receipt of any medications within 1 month prior to dosing or within five half‐lives of any medications at screening; and positivity for hepatitis B, hepatitis C, treponema pallidum infection or human immunodeficiency virus antibodies.
2.2. Study design
This was a randomized, double‐blind, placebo‐controlled Phase 1 trial of HRS‐1893 (ClinicalTrials.gov, NCT05879523), consisting of a single ascending dose (SAD) study, a multiple ascending dose (MAD) study and a food effect (FE) study.
Six dose cohorts were planned for the SAD study, including 5, 15, 30, 50, 75 and an optional dose of 100 mg. For each dose cohort—except for the 30‐mg group—eight subjects were randomized in a 6:2 ratio to receive either HRS‐1893 or placebo at each specified dose level. In the case of the 30 mg cohort, 10 subjects were randomized in an 8:2 ratio to receive HRS‐1893 at 30 mg or placebo. On Day 1, participants received the study medication orally while in a fasted state. Subjects were hospitalized for observation until Day 6 and monitored for safety until Day 13.
The 30‐mg SAD cohort was planned to enter the FE study following a safety assessment conduct at the conclusion of the SAD study. In the absence of unresolved adverse events (AEs), participants were administered either HRS‐1893 30 mg or placebo on the following day, after consuming a high‐fat meal. Conversely, if any AEs remained unresolved, safety follow‐up continued until the investigator determined that the participant could proceed to the FE study or withdraw from participation. The observation and follow‐up period for the FE study were consistent with those in the SAD study.
Four dose cohorts were planned for the MAD study, including 10, 20, 40 and an optional dose of 60 mg. Eight subjects in each dose cohort were randomized in a 6:2 ratio to receive either HRS‐1893 or placebo orally at each dosage level twice daily (BID) over a span of 14 consecutive days. Only one dose was administered on Day 14. Participants were hospitalized for observation until Day 16 and completed safety follow‐up assessment until Day 26.
HRS‐1893 dose selection was based on preclinical data. The starting dose of 5 mg was determined based on the no‐observed‐adverse‐effect level (NOAEL) from the animal models and calculated using the body surface area‐normalization method. The effective dose range of 15 to 80 mg was predicted based on the preclinical potency, efficacy data and PK characterization of HRS‐1893. Considering the exposure at NOAEL and the effective dose, as well as safety of the healthy participants, the maximum dose level was set at an optional 100 mg. Regarding the selection of dosing regimen in MAD cohorts, steady‐state concentration‐time profiles under multiple‐dose regimens were simulated using a population pharmacokinetics model. A BID dosing regimen was selected due to its lower concentration fluctuations at steady state. Additionally, because the changes in LVOT‐G, a relevant therapeutic indicator, could not be characterized in healthy subjects, the pharmacokinetic–pharmacodynamic relationship was investigated in patients with obstructive hypertrophic cardiomyopathy. This study in healthy subjects primarily examined the correlation between exposure levels and the safety indicator LVEF.
Dose escalation in the SAD and MAD studies was decided by a safety monitoring committee comprising investigators and sponsor members. The safety monitoring committee reviewed the available safety data from all subjects in the lower dose level at least 48‐h post‐dose. Dose escalation proceeded if the preceding dose was deemed to be safe. Dose escalation was terminated if any of the following was observed: (1) One or more patients had serious AEs (SAEs) related to HRS‐1893; (2) two or more patients in the same dose cohort reported severe AEs classified under the same system organ class according to the Medical Dictionary for Regulatory Activities; (3) 50% or more of patients in the same dose cohort exhibited moderate or severe AEs associated with HRS‐1893; (4) 25% or more of patients in the same dose cohort had a LVEF of less than 50% or demonstrated a reduction in LVEF percentage greater than 20% from baseline; or (5) an increase in drug exposure was no longer observed with increasing dosage.
The randomization codes were generated by a randomization specialist using statistical software. The HRS‐1893 and placebo tablets were identical in appearance, packaging and labelling. Subjects, investigators, and sponsor personnel involved in clinical assessments were blinded for treatment allocation. Blinding was maintained throughout the trial process until database lock.
The protocol and all amendments were approved by the Clinical Research Ethics Committee of Beijing Anzhen Hospital (Approval Nos. CXHL230024, CXHL2300251 and CXHL2300252). The study was conducted in accordance with the Declaration of Helsinki, Guidelines for Good Clinical Practice, as well as local laws and regulations. All participants provided written informed consent.
2.3. Safety assessments
The primary endpoints of the study were safety and tolerability, which were assessed by AEs, SAEs, physical examinations, vital signs, 12‐lead ECG, echocardiogram and laboratory tests. AEs were continuously monitored throughout the study and classified according to the Medical Dictionary for Regulatory Activities. 15 The severities of AEs were categorized as mild, moderate or severe. Both the SAD study and FE study adhered to an identical safety assessment schedule. Physical examinations and vital signs were assessed daily during the observation period from Days 1 to 6, as well as at the conclusion of follow‐up on Day 13. The 12‐lead ECGs were performed at 2 h prior to dosing, followed by assessments at 1.5‐, 5‐ and 12‐h post‐dose on Day 1, and on Days 2–6 and 13. Laboratory tests were performed on Days 2, 3 and 6. In the MAD study, physical examinations and vital signs were assessed daily throughout the observation period from Days 1 to 16; on Days 17–19 and 26 of the follow‐up period, 12‐lead ECGs were performed at 2 h before each first daily dose from Days 1 to 14; at 1.5‐, 5‐ and 12‐h post‐dose on Day 14; on Days 15–19 and 26, QTcF intervals were assessed only for the 50 and 75 mg SAD cohorts and all MAD cohorts. Laboratory tests were performed on Days 3, 8, 14, 16, 19 and 26.
2.4. PK assessments
The concentrations of HRS‐1893 in plasma and urine were measured for PK analysis. For the SAD and FE studies, blood samples were collected at pre‐dose and 0.5‐, 1‐, 1.5‐, 2‐, 3‐, 5‐, 8‐, 12‐, 24‐, 48‐, 72‐, 96‐ and 120‐h post‐dose. For the MAD study, blood samples were collected at pre‐dose, 0.5‐, 1‐, 1.5‐, 2‐, 3‐, 5‐, 8‐, 12‐, and 24‐h post‐dose on Day 1; within 30 min of the first daily dose on Days 5, 8 and 11–14; and 0.5, 1, 1.5, 2, 3, 5, 8, 12, 24, 48, 72, 96 and 120 h following the last dose administered on Day 14. Urine samples were exclusively collected from the SAD cohorts 15, 30 and 50 mg. As this study represents a preliminary investigation of the urinary PK characteristics of HRS‐1893, the three doses around the effective dose range were selected. Samples were obtained at pre‐dose and 0‐ to 12‐h, 12‐ to 24‐h, 24‐ to 48‐h, 48‐ to 72‐h, 72‐ to 96‐h and 96‐ to 120‐h post‐dose.
Plasma PK parameters were calculated, including area under the concentration‐time curve from zero to last measurable concentration (AUC 0−t ), AUC from zero to infinity (AUC 0–∞), maximum plasma concentration (C max ), time to reach C max (T max ), terminal elimination half‐life (t 1/2), apparent total clearance (CL/F) and apparent volume of distribution (V z /F) following a single dose of HRS‐1893. In the MAD study, AUC during a dosing interval (AUC tau ), T max and C max following the first dose, as well as AUC tau , T max , CL/F, minimum plasma concentration (C min ), C max and accumulation ratio (R ac ) at steady state (Day 8), were calculated. Urine PK parameters included amount excreted (Ae), fraction excreted (fe) and renal clearance (CLr). Plasma and urine concentrations of HRS‐1893 were determined using a validated high‐performance liquid chromatography–tandem mass spectrometry (HPLC‐MS/MS) method at Guochen BioTek. The lower limit of quantitation (LLOQ) was 0.5 ng/ml for plasma samples and 10 ng/ml for urine samples, whereas the upper limit of quantitation (ULOQ) was 1000 ng/ml for both matrices. In plasma concentration analysis, the accuracy was −3.3 ~ 2.5%, and the precision was 4.0 ~ 4.8. In urine concentration analysis, the accuracy was −3.2 ~ 2.8%, and the precision was 5.0 ~ 5.7%.
2.5. PD assessments
PD was assessed exclusively in the SAD and MAD studies. PD endpoints include percentage changes from baseline in LVEF, LV outflow tract velocity time integral (LVOT‐VTI), LV fractional shortening (LVFS) and LV global longitudinal strain (LVGLS) measured by TTE. In the SAD study, PD outcomes were evaluated at 1.5‐, 5‐, 8‐, 24‐, 48‐, 72‐, 96‐ and 120‐h post‐dose, as well as at study completion. In MAD study, PD outcomes were assessed on Days 1, 2, 5, 8, 11 and 14 at 1.5 h following the first daily dose, as well as on Days 15, 16 and 19.
2.6. Statistical analysis
Due to the nature of first‐in‐human Phase 1 studies, no formal statistical hypothesis was established. The sample size was determined primarily based on regulatory requirements and practical considerations. The SAD study aimed to enrol a total of 50 healthy subjects, with 8 participants in each of the cohorts for Doses 5, 15, 50, 75 and 100 mg and 10 participants in 30‐mg cohort. The FE study included the same group of 10 subjects derived from the 30‐mg SAD cohort. The MAD study planned to enrol 32 subjects, with eight in each of the 10‐, 20‐, 40‐ and 60‐mg cohorts.
Safety was analysed in all subjects who had received at least one dose of the study treatment. PK was analysed in all randomized and treated subjects who had at least one PK data. PD analysis was performed on all randomized and treated subjects with a non‐missing baseline and at least one post‐dose PD evaluation data.
Baseline characteristics and safety data were summarized descriptively. The plasma concentration‐time profiles of HRS‐1893 were presented graphically. PK parameters were estimated using a non‐compartmental model and summarized with descriptive statistics. The dose‐exposure proportionality of HRS‐1893 was analysed utilizing PK parameters C max , AUC 0−t and AUC 0–∞ in the SAD study and C max,ss and AUC 0−tau in the MAD study. The geometric mean ratio of PK parameters between two dose levels were calculated, and a linear fitting was conducted using a power model to estimate the slope and its associated 90% confidence interval (CI). The effect of food on HRS‐1893 exposure was analysed using an analysis of variance model, with fed and fasted states as fixed effects and subjects as random effects. Percentage changes in PD outcomes from baseline were summarized by dose cohorts and presented graphically.
PK parameters were calculated using Phoenix WinNonlin (Version 6.3). The other statistical analyses were conducted using SAS (Version 9.4 or higher).
3. RESULTS
3.1. Participants
Between 5 June 2023 to 19 October 2023, 190 Chinese healthy subjects were screened, of which 68 met the eligible criteria and were subsequently randomized (Figure S1). Two subjects withdrew from the study prior to treatment administration due to arrhythmia, including one from the 20‐mg MAD cohort and one from the placebo group. Ultimately, a total of 66 subjects received either HRS‐1893 or placebo, including 32 participants who received a single dose of HRS‐1893 (n = 6 each at 5, 15, 50 and 75 mg; n = 8 at 30 mg), 18 participants who received multiple doses of HRS‐1893 (n = 6 each at 10, 20 and 40 mg) and 16 participants who received placebo. Additionally, two subjects withdrew from the study due to personal reasons (n = 1 in the 50‐mg SAD cohort) and pregnancy (n = 1 in the placebo group). The remaining 64 subjects completed the study. Demographic data and baseline characteristics were generally balanced across both HRS‐1893 dosing cohorts and the placebo group (Table 1).
TABLE 1.
Demographics and baseline characteristics.
| HRS‐1893 SAD cohorts | HRS‐1893 MAD cohorts | Placebo (N = 16) | |||||||
|---|---|---|---|---|---|---|---|---|---|
| 5 mg (N = 6) | 15 mg (N = 6) | 30 mg (N = 8) | 50 mg (N = 6) | 75 mg (N = 6) | 10 mg (N = 6) | 20 mg (N = 6) | 40 mg (N = 6) | ||
| Age, years | 32.7 (3.5) | 32.0 (8.0) | 36.4 (7.1) | 33.3 (7.4) | 34.8 (5.3) | 33.0 (3.5) | 34.8 (5.0) | 31.7 (6.0) | 34.3 (6.8) |
| Sex, n (%) | |||||||||
| Male | 1 (16.7) | 4 (66.7) | 3 (37.5) | 3 (50.0) | 3 (50.0) | 2 (33.3) | 5 (83.3) | 4 (66.7) | 9 (56.3) |
| Female | 5 (83.3) | 2 (33.3) | 5 (62.5) | 3 (50.0) | 3 (50.0) | 4 (66.7) | 1 (16.7) | 2 (33.3) | 7 (43.8) |
| Ethnicity, n (%) | |||||||||
| Han | 5 (83.3) | 6 (100) | 8 (100) | 6 (100) | 6 (100) | 6 (100) | 6 (100) | 6 (100) | 15 (93.8) |
| Others | 1 (16.7) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 (6.3) |
| BMI, kg/m2 | 21.75 (2.38) | 22.55 (1.23) | 22.94 (1.66) | 22.93 (1.18) | 23.35 (2.29) | 23.43 (1.48) | 23.43 (2.32) | 24.53 (2.35) | 22.58 (1.89) |
Note: Data are presented as mean (SD) unless otherwise specified.
Abbreviations: BMI, body mass index; MAD, multiple ascending dose; SAD, single ascending dose; SD, standard deviation.
3.2. Safety and tolerability
All 66 treated subjects were included in the safety analysis. In the SAD study, treatment‐emergent AEs (TEAEs) were reported by 6 (18.8%) out of 32 subjects in HRS‐1893 dose cohorts and 3 (30.0%) out of 10 subjects in the placebo group (Table S1). All TEAEs observed in HRS‐1893‐treated subjects were classified as mild in severity, with only one subject from the 15‐mg cohort experiencing a treatment‐related AE (TRAE), namely, increased gamma‐glutamyl aminotransferase. This AE was classified as HRS‐1893‐related because there was a temporal causality. The increase in gamma‐glutamyl aminotransferase happened after the participant receiving HRS‐1893 treatment; therefore, we could not rule out the possibility that the increase was associated with the treatment. There were no SAEs or TEAEs that resulted in treatment interruption, discontinuation or death following a single dose of HRS‐1893. One subject from the placebo group discontinued treatment and withdrew from the study due to an increase in human chorionic gonadotropin level, which was deemed unrelated to the study medication. In the FE study, one subject in the 30‐mg cohort experienced mild TEAEs—decreased haemoglobin and increased blood creatinine—of which increased blood creatinine was determined to be treatment related. In the MAD study, 8 (44.4%) out of 18 subjects in the HRS‐1893 cohorts and 2 (33.3%) out of 6 subjects in the placebo group reported TEAEs, all of which were classified as mild in severity. Among these, four (22.2%) subjects experienced TEAEs related to HRS‐1893, whereas no subjects in the placebo group reported TRAEs. Importantly, there were no SAEs or TEAEs that resulted in treatment interruption, discontinuation or death during the course of the MAD study. TEAEs observed during the study are presented in Table 2. AEs associated with HRS‐1893 included increased gamma‐glutamyl transferase (1 [3.1%]) in SAD cohort, as well as increased alanine aminotransferase, increased blood creatinine and dizziness (1 [5.6%] for each) in MAD cohort. All biochemical changes were transient and either improved or resolved without corrective treatment. Overall, there were no clinically significant changes in physical examinations, vital signs or 12‐lead ECG (including QTcF) when compared to baseline measurements.
TABLE 2.
TEAEs.
| SAD | HRS‐1893 | Placebo (N = 10) | |||||
|---|---|---|---|---|---|---|---|
| 5 mg (N = 6) | 15 mg (N = 6) | 30 mg (N = 8) | 50 mg (N = 6) | 75 mg (N = 6) | Total (N = 32) | ||
| White blood cell count decreased | 0 | 0 | 2 (25.0) | 0 | 0 | 2 (6.3) | 1 (10.0) |
| Lymphocyte count decreased | 0 | 0 | 0 | 0 | 1 (16.7) | 1 (3.1) | 0 |
| Lipase increased | 0 | 0 | 0 | 0 | 1 (16.7) | 1 (3.1) | 0 |
| Gamma‐glutamyl transferase increased | 0 | 1 (16.7) | 0 | 0 | 0 | 1 (3.1) | 0 |
| Neutrophil count decreased | 0 | 0 | 1 (12.5) | 0 | 0 | 1 (3.1) | 1 (10.0) |
| Blood uric acid increased | 0 | 0 | 0 | 1 (16.7) | 0 | 1 (3.1) | 1 (10.0) |
| Haemoglobin decreased | 0 | 0 | 1 (12.5) | 0 | 0 | 1 (3.1) | 0 |
| Upper respiratory tract infection | 0 | 1 (16.7) | 0 | 0 | 0 | 1 (3.1) | 0 |
| Human chorionic gonadotropin increased | 0 | 0 | 0 | 0 | 0 | 0 | 1 (10.0) |
| MAD | HRS‐1893 | Placebo (N = 6) | |||
|---|---|---|---|---|---|
| 10 mg (N = 6) | 20 mg (N = 6) | 40 mg (N = 6) | Total (N = 18) | ||
| Haemoglobin decreased | 1 (16.7) | 0 | 1 (16.7) | 2 (11.1) | 0 |
| Dizziness | 1 (16.7) | 0 | 1 (16.7) | 2 (11.1) | 0 |
| Alanine aminotransferase increased | 0 | 1 (16.7) | 0 | 1 (5.6) | 0 |
| Low density lipoprotein increased | 0 | 1 (16.7) | 0 | 1 (5.6) | 0 |
| Bile acids increased | 0 | 0 | 1 (16.7) | 1 (5.6) | 0 |
| Blood uric acid increased | 0 | 1 (16.7) | 0 | 1 (5.6) | 0 |
| Blood fibrinogen decreased | 1 (16.7) | 0 | 0 | 1 (5.6) | 0 |
| Blood creatinine increased | 0 | 0 | 1 (16.7) | 1 (5.6) | 0 |
| Blood cholesterol increased | 0 | 1 (16.7) | 0 | 1 (5.6) | 0 |
| Neutrophil count decreased | 0 | 0 | 0 | 0 | 1 (16.7) |
| White blood cell count decreased | 0 | 0 | 0 | 0 | 2 (33.3) |
Note: Data are presented as n (%).
Abbreviations: MAD, multiple ascending dose; SAD, single ascending dose.
Single doses of HRS‐1893 ranging from 5 to 50 mg did not result in significant alterations in LVEF (Figure 1). The SAD cohort receiving 75‐mg HRS‐1893 exhibited a slight decrease in mean LVEF, with the most considerable percentage change from baseline recorded at −4.7%. In the MAD study, LVEF within the placebo group remained stable, whereas mean LVEF in MAD cohorts administrated doses between 10 and 40 mg demonstrated a dose‐dependent decline (Figure 2). Specifically, the 40‐mg MAD cohort had a mean LVEF of 64.8% at baseline, which decreased to 60.2% by Day 5, reflecting a relative percentage reduction of 7.2%. This level of LVEF was maintained around 60% until the last dosing on Day 14 and returned to baseline level by Day 16. Notably, none of the subjects experienced an LVEF below 50% throughout the duration of the study. The relationship between concentration of HRS‐1893 and change in LVEF for SAD and MAD cohorts was illustrated in Figure 3. As plasma concentration of HRS‐1893 increased, a trend towards a reduction in LVEF was observed.
FIGURE 1.
Percentage changes in LVEF following single doses of HRS‐1893. Error bars show standard deviation.
FIGURE 2.
LVEF following multiple doses of HRS‐1893. Error bars show standard deviation.
FIGURE 3.
Relationship between HRS‐1893 plasma concentration and LVEF in the (A) SAD cohorts and (B) MAD cohorts.
3.3. PK characteristics and effect of food on PK
All 50 subjects treated with HRS‐1893 were analysed for PK. The PK parameters following both single and multiple doses of HRS‐1893 are summarized in Table 3.
TABLE 3.
PK parameters of single and multiple doses of HRS‐1893.
| SAD | HRS‐1893 | ||||
|---|---|---|---|---|---|
| 5 mg (N = 6) | 15 mg (N = 6) | 30 mg (N = 8) | 50 mg (N = 6) | 75 mg (N = 6) | |
| T max , h | 1.50 (1.00, 2.00) | 1.75 (1.00, 5.00) | 1.00 (0.500, 2.00) | 1.25 (0.500, 3.00) | 2.00 (0.500, 3.00) |
| C max , ng/ml | 347 (21.6) | 532 (12.7) | 1000 (15.5) | 1080 (14.8) | 1150 (16.5) |
| Median (5th percentile and 95th percentile) | 343 (241, 436) | 514 (454, 644) | 1010 (831, 1350) | 1040 (943, 1340) | 1090 (990, 1430) |
| AUC 0−t , h*ng/ml | 2010 (18.0) | 4580 (14.3) | 6730 (12.0) | 9130 (14.8) | 9710 (17.1) |
| Median (5th percentile, 95th percentile) | 1890 (1710, 2520) | 4740 (3500, 5210) | 6570 (6120, 8910) | 9450 (6990, 10 600) | 10 100 (7710, 11 600) |
| AUC 0–∞, h*ng/ml | 2110 (18.0) | 4790 (13.7) | 7610 (1.9) | 11 000 (7.6) | 11 300 (17.9) |
| Median (5th percentile, 95th percentile) | 1960 (1820, 2660) | 4920 (3700, 5400) | 7590 (7440, 7870) | 10 800 (10 200, 12 200) | 11 900 (9260, 13 100) |
| t 1/2, h | 92.0 (10.5) | 84.5 (9.1) | 68.8 (7.7) | 60.3 (8.3) | 56.4 (7.5) |
| V z /F, L | 313 (24.2) | 380 (17.9) | 389 (12.2) | 393 (17.7) | 538 (31.1) |
| CL/F, ml/min | 39.5 (18.0) | 52.2 (13.7) | 65.7 (1.9) | 75.8 (7.6) | 111 (17.9) |
| Ae, mg | N/A | 10.8 (5.4) | 15.2 (17.0) | 23.6 (26.1) | N/A |
| CLr, ml/min | N/A | 42.6 (11.7) | 37.8 (23.8) | 43.1 (15.9) | N/A |
| fe, % | N/A | 72.1 (5.4) | 50.8 (17.0) | 47.3 (26.1) | N/A |
| MAD | HRS‐1893 | ||
|---|---|---|---|
| 10 mg (N = 6) | 20 mg (N = 6) | 40 mg (N = 6) | |
| T max , h | 2.25 (0.500, 3.00) | 1.25 (0.500, 3.00) | 0.750 (0.500, 3.00) |
| Cmax, ng/ml | 399 (36.2) | 650 (43.3) | 854 (36.4) |
| Median (5th percentile, 95th percentile) | 502 (209, 830) | 804 (344, 1200) | 1100 (434, 1620) |
| AUC tau , h*ng/ml | 1640 (20.1) | 2510 (34.1) | 3180 (55.5) |
| Median (5th percentile, 95th percentile) | 2050 (1170, 4190) | 3560 (1510, 6950) | 5450 (1150, 9990) |
| T max,ss , h | 2.00 (1.00, 3.00) | 1.50 (0.50, 3.00) | 2.25 (0.50, 3.00) |
| C max,ss , ng/ml | 599 (24.8) | 900 (25.7) | 1370 (19.6) |
| AUC tau,ss , h*ng/ml | 2950 (26.9) | 5140 (29.4) | 8380 (19.2) |
| C min,ss , ng/ml | 111 (41.4) | 225 (35.1) | 351 (18.4) |
| CL ss /F, ml/min | 56.5 (26.0) | 64.8 (29.4) | 79.6 (19.2) |
| R ac , Cmax | 1.50 (25.9) | 1.38 (39.9) | 1.60 (19.0) |
| R ac , AUCtau | 1.80 (16.7) | 2.05 (10.9) | 2.63 (36.7) |
Note: T max is presented as median (range); t 1/2 is presented as mean (SD); the other parameters are presented as geometric mean (CV%). The dosing interval tau was 12 h.
Abbreviations: Ae, amount excreted; AUC 0–∞, AUC from zero to infinity; AUC 0−t , area under the concentration‐time profile from zero to last measurable concentration; AUC tau , AUC during a dosing interval; CL/F, apparent total clearance; CLr, renal clearance; C max , maximum plasma concentration; C min , minimum plasma concentration; CV, coefficient of variation; fe, fraction excreted; R ac , ratio of accumulation; SD, standard deviation; ss, steady state; t 1/2, terminal elimination half‐life; T max , time to reach maximum plasma concentration; V z /F, apparent volume of distribution.
In the SAD study, the concentration of HRS‐1893 after single‐dose oral administration was obtained from 32 healthy subjects. The HRS‐1893 was absorbed rapidly, and the increase in exposure over the 5‐ to 75‐mg dose range was less than dose proportional. After a single dose of HRS‐1893 from 5 to 75 mg, the median T max ranged 1.0 to 2.0 h. The geometric mean C max and AUC 0–∞ ranged from 347 to 1150 ng/ml and from 2110 to 11 300 h*ng/ml, respectively, with their coefficient of geometric variation ranging from 12.7% to 21.6% for C max and from 7.6% to 18.0% for AUC 0–∞. The change in plasma concentration of HRS‐1893 showed a two‐compartment pattern, where most of the drug was eliminated from the plasma compartment within the first 24‐h post‐administration, whereas the remaining portion was eliminated at a slower rate (Figure S2).
In the MAD study, HRS‐1893 concentrations were obtained in 18 healthy subjects who received oral administration twice daily. The results showed that steady state was achieved by Day 8 and the increase in exposure was subproportional to the dose proportional. With multiple dosing of HRS‐1893 at doses between 10 and 40 mg, plasma concentrations reached steady state around Day 8. The median T max at steady state was comparable to that observed after the initial dose administration. R ac ranged from 1.38 to 1.60 for C max and from 1.80 to 2.63 for AUC tau . Power model analyses showed that exposure level of HRS‐1893 during both SAD and MAD increased in a less‐than‐dose‐proportional manner as dosage increased (Table S2).
Urinary PK in the SAD cohorts of 15, 30 and 50 mg revealed that the geometric mean Ae ranged from 10.8 to 23.6 mg; the geometric mean CLr ranged between 37.8 and 43.1 ml/min; and the geometric mean fe ranged from 47.3 to 72.1% (Table 3). Notably, the mean Ae of HRS‐1893 exhibited a gradual saturation after approximately 12 h‐post‐dose (Figure S3).
Based on the data of the eight subjects in the 30‐mg SAD cohort, food intake had a limited impact on HRS‐1893 PK characteristics. Compared to the fasted state, the median T max was prolonged by 1 h after a high‐fat meal, whereas the mean t 1/2 remained relatively unchanged (Table S3). Exposure of HRS‐1893 showed a slight increase. The estimated geometric mean ratio for C max , AUC 0−t and AUC 0–∞ in the fed vs. fasted states were 1.12, 1.29 and 1.27, respectively (Table S4).
3.4. Pd
The parameters LVOT‐VTI, LVFS and LVGLS showed no significant changes following a single administration of either HRS‐1893 or placebo (Figure S4). In contrast, with multiple doses of HRS‐1893, there was a noticeable decreasing trend in LVOT‐VTI, LVFS and LVGLS across all of the 10‐, 20‐, and 40‐mg cohorts; however, this reduction did not demonstrate a dose‐dependent relationship (Figure S5). Meanwhile, the PD outcomes remained relatively stable with placebo during the MAD study.
4. DISCUSSION
In this first‐in‐human Phase 1 study, HRS‐1893 was well tolerated in healthy subjects and had a favourable PK profile. The incidence of TEAEs was comparable between the HRS‐1893 and placebo groups. All TEAEs reported in HRS‐1893‐treated subjects were classified as mild in severity, and all TEAEs either improved or resolved without corrective treatment. Notably, there were no cardiovascular AEs, SAEs or TEAEs that resulted in treatment discontinuation or death observed in either the SAD or MAD study.
Single doses of HRS‐1893, ranging from 5 to 75 mg, were rapidly absorbed, achieving maximum plasma concentration within 1.0 to 2.0 h. Dose‐exposure proportionality analysis indicated that the plasma exposure of HRS‐1893 increased in a less‐than‐dose‐proportional manner as the doses ascended from 5 to 75 mg. One potential explanation for this observation is that HRS‐1893 possesses a low solubility, which limits the dissolution of drug at higher doses and leads to saturation in absorption. The bioavailability diminishes with increasing dose levels, resulting in an exposure profile that deviates from linearity with respect to dosage. The CL/F in the SAD study showed a dose‐dependent increase from 5 to 75 mg. This could also be attributed to the low solubility of HRS‐1893, which leads to decreasing bioavailability and less‐than‐proportional increase in exposure with ascending doses and, consequently, an increase in CL/F. This finding was further corroborated by the urine PK data. Within the dose range of 15 to 50 mg, the fe decreased as dosing increased, whereas the CLr remained relatively consistent across different dosing cohorts. The similar CLr indicates comparable renal excretion capacity. The observed decrease in fe can be attributed to the less‐than‐dose‐proportional feature of exposure. This sublinear exposure‐dose relationship is hypothesized to result from the low solubility of HRS‐1893, leading to absorption limit at higher doses. As the dose increases, the oral bioavailability decreases, such that the proportion of drug absorbed into the systemic circulation relative to the total dose decreases. Consequently, the proportion of excreted dose relative to the total dose also decreases, leading to a reduction in fe with increasing dose.
Although HRS‐1893 exhibited a mean t 1/2 ranging from 56.4 to 92.0 h, the concentration‐time curve showed that HRS‐1893 exhibited two‐compartment distribution, and the concentration in post‐24 h has reduced to less than 10% of C max . Because HRS‐1893 is associated with reduction in LVEF, its rapid plasma clearance during the early stage allows for quick elimination in cases of safety concerns. Moreover, the inter‐individual variability in drug exposure for HRS‐1893 was relatively low, with a geometric coefficient of variation around 20%. This lower variability contributes to greater consistency in drug exposure among subjects receiving the same dose and, to some extent, help mitigate potential safety risks and insufficient efficacy caused by variability in drug exposure.
HRS‐1893 achieves a steady‐state plasma concentration within 8 days following multiple doses, allowing weekly dose adjustments. In contrast, Mavacamten requires approximately 40 days to reach steady‐state with adjustments made every 12 weeks, whereas Aficamten attains this state in about 12 days with biweekly adjustments. HRS‐1893 presents a favourable PK profile that supports therapeutic management efficiency. 16 , 17 , 18 Moreover, preliminary metabolite analysis demonstrated that HRS‐1893 is predominantly present in blood and urine as the parent compound, with metabolites accounting for less than 2% in both blood and urine. HRS‐1893 is primarily eliminated in its parent form via the urine, whereas mavacamten undergoes metabolism predominantly through cytochrome P450 (CYP) enzymes including CYP2C19, CYP3A4 and CYP2C9. 19 Concomitant use of other CYP enzyme inhibitors or inducers may affect mavacamten exposure and lead to undesired changes in LVEF. However, HRS‐1893 is less affected, with its exposure being less impacted by CYP enzyme inhibitors or inducers, thus characteristic imposing fewer restrictions on the use of concomitant medications.
Compared to the fasted state, a high‐fat meal increased the C max of HRS‐1893 by 12%, AUC 0−t by 29% and AUC 0–∞ by 27%. The median T max was extended by 1 h, whereas the mean t 1/2 showed no significant difference. As a result, food intake had no significant impact on the PK characteristics of HRS‐1893 at a dosage of 30 mg.
Continuous administration of HRS‐1893 resulted in a slight decrease in LVEF, but none of the subjects had LVEF of less than 50% during the study. The mean LVEF returned to the baseline level after treatment discontinuation. The relationship of exposure of HRS‐1893 and change in LVEF showed that in both SAD and MAD cohorts, LVEF tended to decrease as plasma concentration increased. The slope of this relationship was steeper in the MAD cohort compared to the SAD cohort, which may be attributable to the repeated dosing. This observation will be further investigated in future studies with larger sample sizes. Meanwhile, cardiac indicators, including LVOT‐VTI, decreased with HRS‐1893 at dosage of 10, 20 and 40 mg, suggesting that HRS‐1893 has the potential to improve cardiac functionality while keeping LVEF within safety limits. Although the PD changes observed among healthy volunteers may not be directly extrapolated to HCM patients, these data support the further development of HRS‐1893 in later phase trials. Subsequent studies will be carried out to evaluate the effect of HRS‐1893 on cardiac function in HCM patients.
As a Phase 1 trial, this study had a relatively small sample size and short study duration, which limited the ability to detect less common AEs and evaluate long‐term safety and efficacy. Population PK analysis will be performed in the future to further assess whether there is a difference in PK between males and females, although the available data suggest no such difference. Future studies will be carried out to further assess HRS‐1893 in the target population.
5. CONCLUSION
HRS‐1893, a selective reversible cardiac myosin inhibitor demonstrated acceptable safety and favourable PK profiles among healthy subjects. With the shorter dose titration interval, lower inter‐individual variability and greater control on LVEF, HRS‐1893 becomes a strong candidate for the treatment of obstructive hypertrophic cardiomyopathy.
AUTHOR CONTRIBUTIONS
Conception or design of the work: Kexu Yang, Shan Jing, Wenfang Liu, Yang Lin, Xiaoyi Sun, Meng Fu, Xi Li, Ting Zhang, Min Hu, Feng He and Jun Feng. Acquisition, analysis or interpretation of data: Shan Jing, Kexu Yang, Wenfang Liu, Xiaoyi Sun, Meng Fu and Xi Li. Writing—original draft: Kexu Yang and Wenfang Liu. Writing—review and editing: Shan Jing, Yang Lin, Xiaoyi Sun, Meng Fu, Xi Li, Ting Zhang, Min Hu, Feng He and Jun Feng. All authors have approved the final manuscript and have agreed to be accountable for the submitted work.
CONFLICT OF INTEREST STATEMENT
Xiaoyi Sun, Meng Fu, Xi Li, Ting Zhang, Min Hu, Feng He and Jun Feng are employees of Hengrui. The other authors declare no conflicts of interest.
Supporting information
Figure S1. Subjects disposition.
Figure S2. Plasma concentration‐time profiles of single doses of HRS‐1893.
Figure S3. Amount of HRS‐1893 excreted in the urine.
Figure S4. PD outcomes following single doses of HRS‐1893.
Figure S5. PD outcomes following multiple doses of HRS‐1893.
Table S1. Safety summary.
Table S2. Dose‐proportionality of HRS‐1893.
Table S3. PK parameters of HRS‐1893 after a high‐fat meal.
Table S4. Effect of food on HRS‐1893 PK parameters.
ACKNOWLEDGEMENTS
We are grateful to all participants and their families, the investigators and the site staff. Medical writing support was provided by Xinyu Xie (Medical Writer at Hengrui) according to Good Publication Practice Guidelines.
Yang K, Liu W, Lin Y, et al. Safety, tolerability, pharmacokinetics, pharmacodynamics and food effect of HRS‐1893, a cardiac myosin inhibitor, in healthy subjects. Br J Clin Pharmacol. 2026;92(9):3151‐3160. doi: 10.1002/bcp.70542
Funding information This study was funded by Jiangsu Hengrui Medicine.
The authors confirm that the Principal Investigators for this paper are Yang Lin and Shan Jing and that they had direct clinical responsibility for patients.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request. Some data may not be made available because of privacy or ethical restrictions.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1. Subjects disposition.
Figure S2. Plasma concentration‐time profiles of single doses of HRS‐1893.
Figure S3. Amount of HRS‐1893 excreted in the urine.
Figure S4. PD outcomes following single doses of HRS‐1893.
Figure S5. PD outcomes following multiple doses of HRS‐1893.
Table S1. Safety summary.
Table S2. Dose‐proportionality of HRS‐1893.
Table S3. PK parameters of HRS‐1893 after a high‐fat meal.
Table S4. Effect of food on HRS‐1893 PK parameters.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request. Some data may not be made available because of privacy or ethical restrictions.