Abstract
This study evaluated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and food effects (FE) of SC0062, a highly active endothelin‐A (ETA) receptor antagonist, in healthy subjects. The primary objectives of this first‐in‐human phase I study, comprised of single‐ascending‐dose, multiple‐ascending‐dose, and FE parts, were to characterize the safety and tolerability of SC0062, and FE. The secondary objectives were to determine the PK behavior of SC0062 and its major active metabolite M18, whereas exploratory objectives focused on PD effects, principally effects on endothelin‐1 (ET‐1) and total bile acids (TBA). Single doses of 10 to 100 mg and multiple daily doses of 20 and 50 mg for 6 days were well tolerated. SC0062 was rapidly absorbed and plasma exposure of SC0062 and M18 increased disproportionately with dose, achieving steady state by day 3, with accumulation ratios of 1.22 and 1.89 on day 6 for SC0062 and M18, respectively. The geometric mean (geometric standard deviation) terminal elimination half‐life (t 1/2) values of SC0062 and M18 were 7.25 (1.70) h and 13.73 (1.32) h, respectively. Plasma ET‐1 concentrations were dose‐proportional, whereas plasma TBA concentrations behaved erratically. Following a single 50 mg dose of SC0062 after a high‐fat meal, C max values for SC0062 and M18 increased by 41% and 32%, respectively, and median T max values for SC0062 were 3 h longer than fasting values; exposure was unaffected. These favorable safety, PK, and PD results provide a foundation for further studies of SC0062 in pulmonary arterial hypertension, chronic kidney disease, and other relevant indications.
Study Highlights.
WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
Endothelin (ET) receptor antagonists have demonstrated therapeutic benefit in various medical disorders such as pulmonary arterial hypertension. There is less known about the role of the endothelin ligand–receptor axis in chronic kidney disease, albeit a strong rationale to evaluate selective ETA receptor antagonists like SC0062. The rationale for this first‐in‐human (FIH) study of SC0062 was to provide support for evaluations in chronic kidney disease and other indications.
WHAT QUESTION DID THIS STUDY ADDRESS?
This FIH study characterized the safety, pharmacodynamics (PK), and pharmacodynamics of single‐ and multiple‐ascending doses of the selective ETA receptor antagonist SC0062, as well as the effect of food on its PK.
WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
SC0062 can be administered safety and confers favorable PK at doses that appear to engage with its target.
HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?
The development of a highly selective and potent ETA inhibitor that confers favorable PK and engages with the target at doses that are safe is often associated with clinical relevance and superior therapeutic indices.
INTRODUCTION
Endothelins (ETs), which are 21‐amino acid vasoconstricting peptides produced by vascular endothelial cells, play critical roles in vascular homeostasis, and are implicated in cardiovascular, pulmonary, and chronic kidney disease (CKD), amongst others. 1 There are three isoforms of the ET peptides, known as ET‐1, ‐2, and ‐3, each encoded by a separate gene, with varying regions of expression and binding to at least four known ET receptors (ETA, ETB1, ETB2, and ETC), and regulatory effects on downstream signaling mediated by two G‐protein coupled receptors (ETA and ETB). 2 ETA receptors mediate proliferation and contraction of vascular smooth muscle, while ETB receptors promote release of vasodilators such as nitric oxide and prostaglandins. 3
Several ET receptor antagonists indicated for the treatment of adult pulmonary hypertension, including bosentan, 4 ambrisentan, 5 and macitentan, have undergone regulatory approval. 6 However, the therapeutic applications of ET receptor antagonists are also being evaluated in CKD, such as the ETA antagonist atrasentan in diabetic kidney disease 7 , 8 and IgA nephropathy. 9
SC0062, a highly potent and perhaps the most selective ETA antagonist, is being developed to delay progression of CKD since antagonistic ETA effects are known to reduce renal cell injury and proteinuria and inhibit inflammation and fibrosis, whereas ETB antagonists induce vasoconstriction and other unfavorable effects, particularly in treating CKD. 10 ET‐1 antagonists, especially those selective for ETA, reduce proteinuria and deterioration of renal function in high‐risk patients with various types of CKD, possibly due to their protective effects on podocytes, dilatation of renal vasculature, and reduction of glomerular inflammatory response. 11
The principal objectives of this first‐in‐human (FIH) study of SC0062 were to investigate the safety, tolerability, and pharmacodynamics (PK) of SC0062 and its major active metabolite M18 administered as single‐ (SAD) and multiple‐ascending oral doses (MAD) to healthy subjects and determine the maximum tolerated dose on SAD and MAD schedules. Additionally, the effect of food on the absorption of both SC0062 and M18, as well as their effects on both ET‐1 and total bile acids (TBA), were explored.
METHODS
Study design
This three‐part study, which was performed in healthy volunteers in the inpatient unit of the Phase I Clinical Research and Quality Consistency Center for the Evaluation for Drugs (Shanghai, China), was approved by the National Medical Products Administration and Institutional Review Board and was compliant with the Declaration of Helsinki. All subjects gave written informed consent, and the study was registered on www.chictr.org.cn (ChiCTR:2000038380).
The study consisted of SAD, MAD, and food effects (FE) parts (Figure S1). SC0062 and placebo were supplied to the clinical trial center by Biocity Biopharmaceutics as 10 and 50 mg capsules and stored at 25°C or below. Subjects were examined and interval histories focusing on adverse events (AEs) were obtained daily. Physical examinations, vital signs, laboratory tests (including complete blood counts, electrolytes, chemistries, urinalyses), and electrocardiograms (ECGs) were used to monitor subjects during and after the treatment period. In the SAD part, the timing of the studies included: physical examinations (screening; days –1 and 5), vital signs and ECGs (screening; daily on days –1 to 5); and laboratory tests (screening; days –1, 2, and 5). In the MAD part, physical examinations were performed in screening and on days –1 and 10; vital signs and ECGs were performed in screening and daily on days –1 to 10; and laboratory tests were performed in screening and on days –1, 3, 6, and 10. In the FE part, physical examinations were performed in screening and on days –1 and 10; vital signs and ECGs were performed in screening and daily on days –1 to 10; and laboratory tests were performed in screening and on days –1, 2, 7, and 10. AEs were monitored throughout the study. AE details, including duration, severity, action taken, outcome, and relationship to study drug, were recorded and evaluated by investigators in teams. Initiation of each cohort in the SAD and MAD studies depended on the frequency and severity of AEs in the prior cohort.
All available safety, PK, and PD results were reviewed before dose escalation. Any AE of at least moderate severity in any one of the two subjects in cohort 1 of the SAD study or any severe AE in at least two subjects in the larger cohorts in the SAD and MAD studies halted further enrollment into the cohort.
The SAD part was comprised of six cohorts: 10, 20, 30, 50, 70, and 100 mg. To minimize safety concerns, the first SAD cohort utilized neither randomization nor placebo. Two subjects were administered 10 mg of SC0062. Subsequent cohorts were double‐blinded, randomized, and placebo‐controlled. Fifty eligible subjects, consisting of 10 subjects in each SAD cohort (20, 30, 50, 60, 100 mg), were randomized (8:2) to receive either SC0062 or placebo. Subjects fasted overnight for at least 10 h before administration of SC0062 or placebo. The first meal was served 4 h after SC0062 administration. Additionally, subjects remained in the inpatient unit from days 1 to 5. A final safety evaluation was performed by telephone on day 8.
The MAD part of the study, which consisted of 20 and 50 mg cohorts, was double‐blinded, randomized, and placebo‐controlled. Twelve subjects in each cohort were randomized (10:2) to receive either SC0062 or placebo once daily for 6 days after fasting overnight for at least 10 h and the first meal was served at least 4 h after study drug administration. The subjects remained in the inpatient unit from days 1 to 10. A final safety evaluation was performed by telephone on day 14.
The FE part of the study was designed as a randomized, open‐label, two‐period, two‐sequence, crossover scheme. Twelve subjects were randomly assigned to one of two treatment sequences. Subjects fasted overnight for at least 10 h prior to administration of 50 mg of SC0062, which was selected based on the safety, PK, and PD results in the SAD and MAD studies. Feeding consisted of treatment 30 min after a standardized, high‐fat meal (approx. 922.34 kcal). Drinking water was prohibited for 1 h before and after treatment. The first meal was served at 4 h after SC0062 administration. The washout period between dosing in the fed and fasted periods was at least 96 h, which was based on the clearance of SC0062 and M18. Subjects remained in the inpatient unit from days 1 to 9. A final safety monitoring evaluation was performed by telephone on day 14.
Study population
Healthy adult male or female subjects between the ages of 18 and 40 years with a body mass index (BMI) between 19 and 26 kg/m2 were enrolled. Subjects were determined to be in good general health based on medical histories, physical examinations, vital signs, ECGs, and routine laboratory tests. Those with histories of clinically significant medical, mental health, and/or substance abuse issues, which could confound data interpretation and/or preclude compliance, were ineligible. Subjects who experienced chronic headache or musculoskeletal pain, or had clinical or laboratory evidence of renal dysfunction, hypothyroidism, or tested positive for hepatitis B or C or human immunodeficiency virus were ineligible. Subjects were excluded if they had lost or donated ≥400 mL of blood within 3 months or ≥200 mL within 1 month prior to treatment. Pregnant or lactating females were ineligible.
Pharmacokinetic and pharmacodynamic analyses
In the SAD study, blood sampling to measure SC0062, M18, and ET‐1 was performed pre‐treatment and at 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, and 96 h post‐dose. Sampling was also performed at 10 and 20 min, and 120, 144, and 168 h post‐dose for subjects randomized to the placebo, 10 mg, or 20 mg cohorts. Preliminary PK analyses in these cohorts were used to readjust the PK sampling scheme going forward. In the MAD study, blood was sampled pre‐treatment, and 1, 2, 3, 4, 6, 8, and 12 h post‐treatment on day 1 to measure SC0062, M18, and ET‐1. Blood was also sampled pre‐treatment daily on days 2 to 6, and 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 h post‐dose on day 6. In the FE study, blood sampling for SC0062 and M18 was performed pre‐treatment and 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 h post‐treatment. Blood sampling for TBA was performed pre‐treatment and 1, 2, 3, and 4 h post‐treatment (SAD) and pre‐treatment on days 1 and 6 (MAD).
Blood was collected for all analytes into venipuncture tubes containing potassium ethylenediaminetetraacetic acid and centrifuged at 1600g for 10 min at 4°C. Plasma was separated into 1 mL aliquots and stored at −70°C until analyzed.
Plasma concentrations of SC0062 and M18 were measured using a validated liquid chromatography–tandem mass spectrometry method at Wuxi Apptec (Shanghai, China). The lower limits of assay quantification were 5.00 and 2.00 ng/mL for SC0062 and M18, respectively. The range of assay accuracy was 94.5%–107.0% and assay precision (%CV) was less than 7.2% for both analytes. The carryover values for SC0062 and M18 were less than 5.2% and 4.9%, respectively. Plasma concentrations of ET‐1 and TBA were measured with ET‐1 (Enzo Life Sciences, Shanghai, China) and TBA (Abcam, Shanghai, China) commercial enzyme‐linked immunosorbent assay (ELISA) kits. The calibration curves ranged from 0.78 to 100 pg/mL and 480 to 2400 nM for ET‐1 and TBA, respectively.
PK parameters of SC0062 and M18 were determined by either inspection or calculated using standard non‐compartmental method with WinNonlin® V8.3.1 (Certara, Princeton, USA). PK parameters included maximum plasma concentration (C max), time of maximum plasma concentration (T max), terminal elimination half‐life (t 1/2), area under the plasma concentration–time curve (AUC) from time zero to 24 h (AUC0–24h), AUC from time zero to time t (AUClast), AUC from time zero to extrapolated infinite time (AUCinf), apparent volume of distribution (Vd/F), apparent clearance (CL/F), maximum steady‐state plasma concentration (C max,ss), time of maximum steady‐state plasma concentration (T max,ss), minimum steady‐state plasma concentration (C min,ss), average steady‐state plasma concentration (Cav,ss), AUC over a dosing interval (AUCtau), and accumulation ratio (Rac).
Values for AUC from time zero to 24 h (AUEC0–24h) were calculated for ET‐1, whereas plasma TBA concentrations were assessed descriptively.
Statistical analyses
No formal hypothesis testing was performed. Sample sizes were based on clinical considerations. Relevant demographic parameters, baseline characteristics, and AEs were described and compiled using SAS® 9.4 (SAS Institute, Raleigh, North Carolina, USA). Continuous variables were summarized using descriptive statistics represented by mean, median, and minimum–maximum values, standard deviation (SD), geometric mean, and standard deviation of the geometric mean. Categorical or discrete variables were summarized using frequency distributions of the numbers and percentages of subjects or events in a category. Log transformation was applied to PK parameters and 90% confidence intervals were calculated whenever required.
To assess dose proportionality, a power model was fit to log‐transformed C max and AUClast values of SC0062 and M18 in the SAD study with the log‐transformed SC0062 dose level (10–100 mg) as the covariate. The slope (~1) was used as a reference to assess the proportionality between PK parameters and dose level.
To evaluate the steady state, the geometric mean (standard deviation) for Cpre‐dose on day 3 to day 6 in each dose group were provided based on data in the MAD study. To assess the effect of food on SC0062 and M18, a mixed‐effects model was fit to the log‐transformed C max, AUCinf, and AUClast values for SC0062 and M18 in FE study during fasting, with the sequence as a fixed effect, and the subject as a random effect. The ratio of the geometric least square of the means (fed/fasted) and corresponding 90% confidence interval (90% CI) values were provided. Median differences between T max in the fed and fasted states were compared using the Wilcoxon method.
RESULTS
Study population
A total of 88 subjects were enrolled, including 52, 24, and 12 subjects into the SAD, MAD, and FE studies, respectively. Relevant demographic and baseline characteristics are summarized in Table 1. The age of subjects in the SAD, MAD, and FE studies were similar, averaging 29.0, 30.2, and 27.8 years, respectively, whereas the percentage of males were 94%, 88%, and 83%. Weight, height, and BMI values were similar in subjects in the SAD, MAD, and FE studies.
TABLE 1.
Demographic and baseline characteristics of subjects in the single‐ascending‐dose, multiple‐ascending‐dose, and food effects parts of the study.
| Cohort (n) | Age, years [mean (SD)] | Sex [n (%)] | Weight, kg [mean (SD)] | Height, cm [mean (SD)] | BMI, kg/m2 [mean (SD)] | ||
|---|---|---|---|---|---|---|---|
| Male | Female | Male | Female | ||||
| Single dose | |||||||
| Placebo (n = 10) | 25.5 (5.8) | 10 (100) | 0 (0) | 63.5 (5.2) | NA | 168.1 (4.7) | 22.5(1.6) |
| 10 mg (n = 2) | 32.5 (6.4) | 2 (100) | 0 (0) | 65.6 (0.8) | NA | 170.5 (0.7) | 22.6 (0.5) |
| 20 mg (n = 8) | 31.3 (4.3) | 7 (88) | 1 (13) | 61.5 (7.6) | 67.1 (NA) | 167.8 (6.3) | 22.6 (0.5) |
| 30 mg (n = 8) | 31.8 (2.5) | 7 (88) | 1 (13) | 66.5 (4.4) | 62.1 (NA) | 170.1 (6.9) | 22.8 (1.5) |
| 50 mg (n = 8) | 30.5 (5.8) | 7 (88) | 1 (13) | 67.0 (7.4) | 64.2 (NA) | 170.4 (4.9) | 22.9 (2.0) |
| 70 mg (n = 8) | 26.6 (5.7) | 8 (100) | 0 (0) | 65.9 (8.0) | NA | 170.5 (4.5) | 22.7 (2.4) |
| 100 mg (n = 8) | 28.5 (4.3) | 8 (100) | 0 (0) | 64.5 (3.3) | NA | 168.5 (2.5) | 22.7 (1.3) |
| Overall (n = 52) | 29.0 (5.3) | 49 (94) | 3 (6) | 64.8 (6.0) | 64.8 (2.5) | 169.3 (4.9) | 22.6 (1.7) |
| Multiple dose | |||||||
| Placebo (n = 4) | 30.0 (5.8) | 3 (75) | 1 (25) | 58.5 (2.4) | 53.5 (NA) | 162.3 (4.3) | 21.8 (1.5) |
| 20 mg (n = 10) | 32.7 (4.7) | 10 (100) | 0 (0) | 66.4 (6.8) | NA | 172.0 (6.7) | 22.4 (1.9) |
| 50 mg (n = 10) | 27.7 (3.5) | 8 (80) | 2 (20) | 66.5 (7.1) | 56.3 (6.9) | 166.4 (6.7) | 23.3 (2.4) |
| Overall (n = 24) | 30.2 (4.8) | 21 (88) | 3 (13) | 65.9 (6.9) | 55.3 (5.1) | 168.0 (7.2) | 22.7 (2.1) |
| Food effect | |||||||
| Fasting‐fed a (n = 6) | 29.3 (3.1) | 6 (100) | 0 (0) | 61.3 (8.5) | NA | 166.5 (5.2) | 22.0 (1.9) |
| Fed‐fasting a (n = 6) | 26.3 (3.3) | 4 (67) | 2 (33) | 60.9 (8.4) | 54.8 (7.7) | 160.4 (5.8) | 22.8 (2.1) |
| Overall (n = 12) | 27.8 (3.4) | 10 (83) | 2 (17) | 61.2 (8.0) | 54.8 (7.7) | 163.5 (6.1) | 22.4 (2.0) |
Abbreviations: BMI, body mass index; n, number of subjects; NA, not available; SD, standard deviation.
Six subjects each were administered SC0062 in either fasting or fed states and then each crossed over to the alternate condition.
Safety
Single doses of SC0062 ranging from 10 to 100 mg and multiple doses of 20 and 50 mg daily for 6 days were well tolerated. All 64 subjects receiving a single dose of SC0062 or placebo in the SAD and FE studies completed all planned safety, PK, and PD evaluations, whereas three subjects in the MAD study did not complete drug administration and/or all planned safety, PK, and PD assessments. Two of the three subjects withdrew due to AEs, including a foot infection (50 mg cohort) and anxiety related to venipuncture (placebo cohort). The third subject withdrew consent for personal reasons (50 mg cohort). No subject was required replacement.
In the SAD and MAD studies, 48 (65%) and 11 (78.6%) subjects receiving SC0062, respectively, experienced at least one treatment emergent AE (TEAE). In the FE study, 7 (58.3%) and 7 (58.3%) subjects had at least one TEAE following feeding and fasting, respectively. TEAEs occurring in any cohort of the study are displayed in Table 2. All TEAEs were mild or moderate in severity. The most common TEAEs were headache and fatigue, which occurred in both SC0062‐ and placebo‐treated subjects in all study parts. Of note, mild and asymptomatic cardiac TEAEs, namely sinus bradycardia and atrioventricular conduction block (first‐degree), were noted in subjects receiving placebo and SC0062 alike.
TABLE 2.
Summary of all treatment‐emergent adverse events (TEAEs) in the single‐ascending‐dose, multiple‐ascending‐dose, and food effects parts of the study. a , b
| Placebo (n = 14) | Single‐ascending dose (n) | Multiple‐ascending dose (n) | Food effect (n) | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 10 mg (n = 2) | 20 mg (n = 8) | 30 mg (n = 8) | 50 mg (n = 8) | 70 mg (n = 8) | 100 mg (n = 8) | Overall (n = 42) | 20 mg (n = 10) | 50 mg (n = 10) | Overall (n = 20) | 50 mg, fasted (n = 12) | 50 mg, fed (n = 12) | ||
| Subjects with any TEAEs | 11 (79) | 1 (50) | 6 (75) | 4 (50) | 6 (75) | 4 (50) | 5 (63) | 26 (62) | 6 (60) | 8 (80) | 14 (70) | 7 (58) | 7 (58) |
| Nervous system disorders | |||||||||||||
| Lethargy | 1 (7) | 0 (0) | 2 (25) | 1 (13) | 1 (13) | 0 (0) | 0 (0) | 4 (10) | 0 (0) | 2 (20) | 2 (10) | 1 (8) | 3 (25) |
| Headache | 2 (14) | 0 (0) | 0 (0) | 0 (0) | 1 (13) | 1 (13) | 2 (25) | 4 (10) | 2 (20) | 8 (80) | 10 (50) | 5 (42) | 3 (25) |
| Head discomfort | 0 (0) | 0 (0) | 1 (13) | 3 (38) | 0 (0) | 0 (0) | 0 (0) | 4 (10) | 0 (0) | 0 (0) | 0 (0) | 2 (17) | 1 (8) |
| Dizziness | 0 (0) | 0 (0) | 1 (13) | 0 (0) | 0 (0) | 1 (13) | 1 (13) | 3 (7) | 2 (20) | 1 (10) | 3 (15) | 0 (0) | 0 (0) |
| Respiratory, thoracic, and mediastinal disorders | |||||||||||||
| Nasal obstruction | 2 (14) | 1 (50) | 2 (25) | 0 (0) | 1 (13) | 1 (13) | 0 (0) | 5 (12) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Epistaxis | 1 (7) | 0 (0) | 0 (0) | 2 (25) | 0 (0) | 0 (0) | 0 (0) | 2 (5) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (8) |
| Oropharyngeal pain | 1 (7) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (13) | 1 (2) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Rhinorrhoea | 0 (0) | 0 (0) | 1 (13) | 0 (0) | 1 (13) | 0 (0) | 0 (0) | 2 (5) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Oropharyngeal discomfort | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (13) | 1 (2) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Investigations | |||||||||||||
| Blood bilirubin increased | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (13) | 0 (0) | 1 (13) | 2 (5) | 0 (0) | 1 (10) | 1 (5) | 0 (0) | 0 (0) |
| White blood cell count decreased | 0 (0) | 0 (0) | 1 (13) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (2) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Bilirubin conjugated increased | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (13) | 1 (2) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Lymphocyte count decreased | 0 (0) | 0 (0) | 1 (13) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (2) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| White blood cells urine‐positive | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (13) | 1 (2) | 0 (0) | 1 (10) | 1 (5) | 0 (0) | 0 (0) |
| Aspartate aminotransferase increased | 1 (7) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Electrocardiogram QT prolonged | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (13) | 0 (0) | 0 (0) | 1 (2) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Blood triglycerides increased | 2 (14) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (10) | 1 (5) | 0 (0) | 1 (8) |
| Hemoglobin decreased | 0 (0) | 0 (0) | 1 (13) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (2) | 1 (10) | 0 (0) | 1 (5) | 0 (0) | 0 (0) |
| Blood creatine phosphokinase myocardial band increased | 1 (7) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Blood creatine phosphokinase increased | 1 (7) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Blood pressure decreased | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (13) | 0 (0) | 1 (2) | 0 (0) | 1 (10) | 1 (5) | 0 (0) | 0 (0) |
| Neutrophil count decreased | 0 (0) | 0 (0) | 1 (13) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (2) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Electrocardiogram PR shortened | 1 (7) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (10) | 1 (5) | 1 (8) | 0 (0) |
| Alanine aminotransferase increased | 1 (7) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Heart rate decreased | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (10) | 0 (0) | 1 (5) | 0 (0) | 0 (0) |
| Blood fibrinogen increased | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (10) | 1 (5) | 0 (0) | 0 (0) |
| White blood cell count increased | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (8) |
| Lymphocyte count increased | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (8) |
| Neutrophil count increased | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (8) |
| Cardiac disorders | |||||||||||||
| Sinus bradycardia | 3 (21) | 0 (0) | 0 (0) | 0 (0) | 1 (13) | 1 (13) | 0 (0) | 2 (5) | 2 (20) | 0 (0) | 2 (10) | 1 (8) | 0 (0) |
| Atrioventricular block (first‐degree) | 2 (14) | 0 (0) | 0 (0) | 0 (0) | 1 (13) | 1 (13) | 0 (0) | 2 (5) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Defect conduction intraventricular | 2 (14) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 3 (30) | 0 (0) | 3 (15) | 0 (0) | 0 (0) |
| General disorders and administration site conditions | |||||||||||||
| Feeling hot | 0 (0) | 0 (0) | 2 (25) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 2 (5) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Asthenia | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (13) | 1 (13) | 2 (5) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Chest pain | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (13) | 0 (0) | 0 (0) | 1 (2) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Pyrexia | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (10) | 0 (0) | 1 (5) | 0 (0) | 0 (0) |
| Gastrointestinal disorders | |||||||||||||
| Abdominal pain | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (13) | 1 (13) | 2 (5) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Diarrhea | 1 (7) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (13) | 1 (2) | 0 (0) | 1 (10) | 1 (5) | 0 (0) | 0 (0) |
| Constipation | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (13) | 0 (0) | 1 (2) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Nausea | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (13) | 1 (2) | 0 (0) | 0 (0) | 0 (0) | 1 (8) | 1 (8) |
| Mouth ulceration | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (13) | 0 (0) | 1 (2) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Vomiting | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (13) | 1 (2) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Musculoskeletal and connective tissue disorders | |||||||||||||
| Neck pain | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 3 (30) | 3 (15) | 0 (0) | 0 (0) |
| Pain in extremity | 0 (0) | 0 (0) | 1 (13) | 0 (0) | 0 (0) | 0 (0) | 1 (13) | 2 (5) | 0 (0) | 1 (10) | 1 (5) | 0 (0) | 0 (0) |
| Back pain | 0 (0) | 0 (0) | 0 (0) | 1 (13) | 0 (0) | 0 (0) | 0 (0) | 1 (2) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Arthralgia | 1 (7) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Myalgia | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (10) | 0 (0) | 1 (5) | 0 (0) | 0 (0) |
| Skin and subcutaneous tissue disorders | |||||||||||||
| Hyperhidrosis | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (13) | 1 (2) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Dermatitis allergic | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (13) | 1 (2) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Rash | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (13) | 1 (2) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Pruritus | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (13) | 0 (0) | 1 (2) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Seborrhoeic dermatitis | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (10) | 0 (0) | 1 (5) | 0 (0) | 0 (0) |
| Urticaria | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (8) |
| Ear and labyrinth disorders | |||||||||||||
| Tinnitus | 0 (0) | 0 (0) | 1 (13) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (2) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Ear pain | 1 (7) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Eye disorders | |||||||||||||
| Eye pain | 0 (0) | 0 (0) | 0 (0) | 1 (13) | 0 (0) | 0 (0) | 0 (0) | 1 (2) | 0 (0) | 1 (10) | 1 (5) | 0 (0) | 0 (0) |
| Eye swelling | 0 (0) | 0 (0) | 0 (0) | 1 (13) | 0 (0) | 0 (0) | 0 (0) | 1 (2) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Infections and infestations | |||||||||||||
| Urinary tract infection | 0 (0) | 0 (0) | 1 (13) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (2) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Localized infection | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (10) | 1 (5) | 0 (0) | 0 (0) |
| Reproductive system and breast disorders | |||||||||||||
| Breast pain | 0 (0) | 0 (0) | 1 (13) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (2) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Psychiatric disorders | |||||||||||||
| Fear of injection | 1 (7) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
Abbreviations: n, number of subjects; TEAE, treatment‐emergent adverse effect.
Medical Dictionary for Regulatory Activities (MedDRA) preferred term (safety analysis set).
Data are expressed as n (%).
Pharmacokinetics
In the SAD study, plasma SC0062 concentrations were obtained from all 52 healthy subjects who received active drug. The plasma concentration–time profiles of SC0062 and M18 are shown in Figure 1a,b, whereas PK parameter estimates are displayed in Table 3. The geometric mean (geometric SD) time to maximum concentration (T max) after a single oral dose was 3.79 (1.36) h and ranged from 2.00 to 8.00 h, whereas T max values for M18 were longer, reaching 11.12 (1.38) h and ranged from 6.00 to 24.00 h. SC0062 did not exhibit linear PK, with less than proportionate increases in C max. and AUC values when administered as a single dose between 10 and 100 mg. In the power model, the slopes of SC0062 C max and AUClast values were 0.66 (90% CI, 0.56–0.76) and 0.87 (90% CI, 0.76–0.97), respectively. The slopes of M18 C max and AUClast were 0.75 (90% CI, 0.64–0.86) and 0.82 (90% CI, 0.74–0.91), respectively. The geometric mean (geometric SD) t 1/2 values for SC0062 and M18 were 7.25 (1.70) and 13.73 (1.32) h, respectively. In the SAD study, the geometric mean (geometric SD) apparent clearance (CL/F) values of SC0062 at 10 and 100 mg were 4.53 (1.06) and 5.36 (1.29) L/h, respectively, whereas the apparent volume of distribution (Vd/F) were 31.8 (1.23) and 93.6 (1.84) L.
FIGURE 1.
Mean (standard deviation) plasma concentration–time profiles (semi‐log) as a function of SC0062 dose in the single‐ascending‐dose (SAD) and multiple‐ascending‐dose (MAD) studies. Pharmacokinetics (PK) profiles of (a) SC0062 in the SAD study, (b) M18 in the SAD study, (c) SC0062 in the MAD study, and (d) M18 in the MAD study.
TABLE 3.
Single‐ascending doses: geometric mean (geometric standard deviation) pharmacokinetic estimates of SC0062 and M18.
| PK parameter (unit) | SC0062 dose | Overall b (n = 42) | |||||
|---|---|---|---|---|---|---|---|
| 10 mg (n = 2) | 20 mg (n = 8) | 30 mg (n = 8) | 50 mg (n = 8) | 70 mg (n = 8) | 100 mg (n = 8) | ||
| SC0062 | |||||||
| T max (h) a | 3.50 (3.00–4.00) | 4.00 (4.00–6.00) | 3.50 (2.00–4.00) | 4.00 (3.00–6.00) | 4.00 (2.00–6.00) | 4.00 (2.00–8.00) | 3.79 (1.36) |
| C max (ng/mL) | 253 (1.12) | 532 (1.25) | 741 (1.11) | 922 (1.41) | 1264 (1.34) | 1381 (1.30) | – |
| AUC0–24h (ng/mL*h) | 2113 (1.09) | 4919 (1.26) | 6364 (1.23) | 8407 (1.38) | 12,353 (1.35) | 14,119 (1.32) | – |
| AUClast (ng/mL*h) | 2113 (1.09) | 4919 (1.26) | 6599 (1.26) | 9674 (1.43) | 14,050 (1.34) | 18,188 (1.29) | – |
| AUCinf (ng/mL*h) | 2209 (1.06) | 5183 (1.27) | 6830 (1.25) | 9888 (1.42) | 14,341 (1.33) | 18,657 (1.29) | – |
| t 1/2 (h) | 4.87 (1.16) | 4.91 (1.21) | 5.47 (1.66) | 8.29 (1.62) | 8.20 (1.37) | 12.11 (1.86) | 7.25 (1.70) |
| CL/F (L/h) | 4.53 (1.06) | 3.86 (1.27) | 4.39 (1.25) | 5.06 (1.42) | 4.88 (1.33) | 5.36 (1.29) | 4.67 (1.32) |
| Vd/F (L) | 31.8 (1.23) | 27.3 (1.27) | 34.7 (1.68) | 60.5 (1.65) | 57.8 (1.59) | 93.6 (1.84) | 48.9 (1.87) |
| M18 | |||||||
| T max (h) a | 8.00 (8.00–8.00) | 12.00 (8.00–12.00) | 12.00 (6.00–24.00) | 12.00 (12.00–24.00) | 12.00 (8.00–12.00) | 10.00 (8.00–24.00) | 11.12 (1.38) |
| C max (ng/mL) | 67.4 (1.20) | 175 (1.20) | 241 (1.28) | 309 (1.47) | 397 (1.25) | 533 (1.30) | – |
| AUC0–24h (ng/mL*h) | 1239 (1.20) | 3187 (1.17) | 4268 (1.25) | 5543 (1.42) | 7158 (1.21) | 9182 (1.26) | – |
| AUClast (ng/mL*h) | 2077 (1.16) | 5804 (1.26) | 7418 (1.13) | 10,639 (1.32) | 13,530 (1.15) | 19,809 (1.19) | – |
| AUCinf (ng/mL*h) | 2135 (1.16) | 5872 (1.26) | 7538 (1.14) | 10,835 (1.32) | 13,712 (1.15) | 20,961 (1.22) | – |
| t 1/2 (h) | 12.30 (1.00) | 13.52 (1.17) | 12.29 (1.25) | 13.02 (1.27) | 12.89 (1.22) | 18.00 (1.51) | 13.73 (1.32) |
Abbreviations: AUC0–24h, area under the plasma concentration–time curve from time zero to 24 h; AUClast, area under the plasma concentration–time curve from time zero to time of last measurable concentration; AUCinf, area under the plasma concentration–time curve from time zero to infinity; C max, maximum plasma concentration; CL/F, apparent total clearance from plasma; GeoMean, geometric mean; GSD, geometric standard deviation; PK, pharmacokinetics; T max, time to maximum plasma concentration; t 1/2, elimination half‐life; Vd/F, apparent volume of distribution.
T max is reported as median (minimum–maximum).
GeoMean (GSD) disclosed for applicable PK parameters.
In the MAD study, SC0062 plasma concentrations were sampled from 20 healthy subjects. The plasma concentration–time profiles of both SC0062 and M18 are shown in Figure 1c,d and PK parameter estimates are displayed in Table 4. Visual inspection of the Cpre‐dose data from days 3 to 6 demonstrated that steady‐state plasma concentrations of SC0062 and M18 were achieved on approximately day 3 (Table S1). There was no apparent accumulation in SC0062 plasma concentrations; the geometric mean (geometric SD) accumulation ratios for C max (RacCmax) were 1.21 (1.11) and 1.11 (1.28) after 6 days in subjects receiving 20 and 50 mg, respectively., while comparable values for AUC (RacAUC) were 1.19 (1.14) and 1.22 (1.21). There was minor accumulation of M18 following 6 days of treatment with respective RacCmax values of 1.63 (1.17) and 1.70 (1.25) at the 20 and 50 mg dose levels, whereas RacAUC values were 1.80 (1.14) and 1.89 (1.22).
TABLE 4.
Multiple‐ascending doses: geometric mean (geometric standard deviation) pharmacokinetic estimates of SC0062 and M18.
| PK parameter (unit) | SC0062 dose | |||
|---|---|---|---|---|
| 20 mg (n) | 50 mg (n) | |||
| Day 1 (n = 10) | Day 6 (n = 10) | Day 1 (n = 10) | Day 6 (n = 8) | |
| SC0062 | ||||
| T max (h) a | 5.00 (3.00–6.00) | 4.00 (3.00–6.00) | 4.00 (2.00–10.00) | 4.00 (3.00–8.00) |
| C max (ng/mL) | 492 (1.13) | 597 (1.18) | 996 (1.43) | 1241 (1.36) |
| C min,ss (ng/mL) | – | 35.2 (2.13) | – | 112 (2.37) |
| C av,ss (ng/mL) | – | 258 (1.27) | – | 544 (1.41) |
| AUCtau (ng/mL*h) | 5182 (1.20) | 6185 (1.27) | 9431 (1.47) | 13,051 (1.41) |
| t 1/2 (h) | – | 5.50 (1.26) | – | 6.44 (1.40) |
| RacAUC | – | 1.19 (1.14) | – | 1.22 (1.21) |
| RacCmax | – | 1.21 (1.11) | – | 1.11 (1.28) |
| M18 | ||||
| T max (h) a | 10.00 (10.00–12.00) | 10.00 (8.00–10.00) | 10.00 (6.00–24.00) | 9.00 (6.00–12.00) |
| C max (ng/mL) | 161 (1.19) | 262 (1.17) | 331 (1.40) | 604 (1.31) |
| C min,ss (ng/mL) | – | 146 (1.18) | – | 336 (1.34) |
| C av,ss (ng/mL) | – | 211 (1.17) | – | 474 (1.28) |
| AUCtau (ng/mL*h) | NA | 5064 (1.17) | 6516 (1.24) | 11,369 (1.28) |
| t 1/2 (h) | – | 13.37 (1.12) | – | 14.80 (1.23) |
| RacAUC | – | 1.80 (1.14) | – | 1.89 (1.22) |
| RacCmax | – | 1.63 (1.17) | – | 1.70 (1.25) |
Abbreviations: AUCtau, area under the plasma concentration–time curve during a dosage interval (for day 1, AUCtau is equivalent to AUC0–24h); C max, maximum plasma concentration; C min,ss, minimum steady‐state concentration in a dosage interval; Cav,ss, average steady‐state concentration (multiple‐dose); NA, not available; PK, pharmacokinetics; RacAUC, accumulation ratio calculated from AUCtau and AUC0–24h after a single dose; RacCmax, accumulation ratio calculated from steady‐state C max and C max after a single dose; T max, time to maximum plasma concentration; t 1/2, elimination half‐life.
T max is reported as median (minimum–maximum).
In the FE study, although C max values for both SC0062 and M18 were higher in most subjects when SC0062 was administered in the fed state, these differences were minor and neither AUClast nor AUCinf values were affected by food (Figure S2). Table 5 summarizes the PK parameters of SC0062 and M18 following fasting and feeding, whereas primary exposure parameter (C max, AUClast, and AUCinf) estimates are summarized based on a mixed‐effects model (Table 6). In this model, administration of SC0062 after feeding was associated with a 40.98% (90% CI, 128.78%, 154.32%) increase in C max; however, AUClast and AUCinf values were negligibly affected, increasing by 3% (90% CI, 95.37%, 111.64%) and 2% (90% CI, 94.50%, 109.30%), respectively. C max, AUClast, and AUCinf values for M18 increased by 31.67% (90% CI, 119.43%, 145.17%), 8.05% (90% CI, 102.90%, 113.45%), and 5.92% (90% CI, 100.88%, 111.21%), respectively. Administration of SC0062 after feeding was associated with a 3‐h prolongation in the T max of SC0062 (p < 0.01), whereas T max values for M18 were not affected (p = 0.85).
TABLE 5.
Food effect: geometric mean (geometric sstandard deviation) pharmacokinetic estimates of SC0062 and M18.
| PK parameter (unit) | Dose (fasting or fed) | |
|---|---|---|
| 50 mg Fasting (n = 12) | 50 mg Fed (n = 12) | |
| SC0062 | ||
| T max (h) a | 5.00 (2.00–8.00) | 8.00 (6.00–12.00) |
| C max (ng/mL) | 1024 (1.29) | 1444 (1.25) |
| AUC0–24h (ng/mL*h) | 10,641 (1.39) | 12,771 (1.31) |
| AUClast (ng/mL*h) | 12,910 (1.40) | 13,321 (1.36) |
| AUCinf (ng/mL*h) | 13,191 (1.39) | 13,710 (1.37) |
| t 1/2 (h) | 10.29 (1.54) | 4.81 (1.26) |
| CL/F (L/h) | 3.79 (1.39) | 3.65 (1.37) |
| Vd/F (L) | 56.2 (1.53) | 25.3 (1.21) |
| M18 | ||
| T max (h) a | 12.00 (8.00–24.00) | 11.00 (10.00–24.00) |
| C max (ng/mL) | 324 (1.21) | 426 (1.18) |
| AUC0–24h (ng/mL*h) | 5756 (1.19) | 6702 (1.16) |
| AUClast (ng/mL*h) | 12,341 (1.19) | 13,334 (1.21) |
| AUCinf (ng/mL*h) | 12,789 (1.19) | 13,546 (1.22) |
| t 1/2 (h) | 16.55 (1.30) | 13.46 (1.17) |
Abbreviations: AUC0–24h, area under the plasma concentration–time curve from time zero to 24 h; AUClast, area under the plasma concentration–time curve from time zero to time of last measurable concentration; AUCinf, area under the plasma concentration–time curve from time zero to infinity; CV, coefficient of variability; C max, maximum plasma concentration; CL/F, apparent total clearance from plasma; PK, pharmacokinetics; T max, time to maximum plasma concentration; t 1/2, elimination half‐life; Vd/F, apparent volume of distribution.
T max is reported as median (minimum–maximum).
TABLE 6.
Food effect: geometric least square of the mean pharmacokinetic estimates for SC0062 and M18 based on a mixed‐effects model.
| Analyte | PK parameter (unit) | Geometric least square of the mean | Geometric least square of the mean (fed/fasted) | ||||
|---|---|---|---|---|---|---|---|
| n | Fasted | n | Fed | Ratio (%) | 90% CI (%) | ||
| SC0062 | C max (ng/mL) | 12 | 1024 | 12 | 1444 | 140.98 | 128.78, 154.34 |
| AUClast (ng/mL*h) | 12 | 12,910 | 12 | 13,321 | 103.18 | 95.37, 111.64 | |
| AUCinf (ng/mL*h) | 12 | 13,191 | 12 | 13,406 | 101.63 | 94.50, 109.30 | |
| T max (h) a | 12 | 5.00 | 12 | 8.00 | 3.01 | p < 0.01 | |
| M18 | C max (ng/mL) | 12 | 324 | 12 | 426 | 131.67 | 119.43, 145.17 |
| AUClast (ng/mL*h) | 12 | 12,341 | 12 | 13,334 | 108.05 | 102.90, 113.45 | |
| AUCinf (ng/mL*h) | 11 | 12,789 | 12 | 13,546 | 105.92 | 100.88, 111.21 | |
| T max (h) a | 12 | 12.00 a | 12 | 11.00 a | 0 b | p = 0.85 b | |
Abbreviations: AUClast, area under the plasma concentration–time curve from time zero to time of last measurable concentration; AUCinf, area under the plasma concentration–time curve from time zero to infinity; CI, confidence interval; C max, maximum plasma concentration; PK, pharmacokinetics; T max, time to maximum plasma concentration.
Median values are shown for T max.
Median differences and p values are shown.
Pharmacodynamics
There were no clear relationships between SC0062 and plasma ET‐1 concentrations in the SAD study. However, a dose–exposure relationship was observed in both SC0062 dose cohorts in the MAD part of the study. AUEC0–24h values for plasma ET‐1 averaged 1.58‐ and 1.83‐fold higher on day 6 in subjects treated with SC0062 at the 20 and 50 mg dose levels compared with those receiving placebo (Table S2 and Figure S3).
No clear relationship between SC0062 dose levels or relevant PK parameters and plasma TBA concentrations was observed in the SAD and MAD parts of the study.
DISCUSSION
The ET axis has been implicated in the pathogenesis of pulmonary, cardiovascular, and kidney diseases, and several selective ET antagonists were recently approved to treat pulmonary arterial hypertension (PAH). 12 The principal focus of ETA development in CKD has been selective ETA antagonists that prevent binding of ET‐1 to ETA, resulting in vasoconstriction, inflammation, cellular injury, fibrosis, and, finally, to proteinuria and renal dysfunction, whereas ET binding to ETB triggers beneficial effects such as vasodilation. Hence inhibiting ETB may not be a suitable therapeutic strategy, which, in part, supports the rationale for developing ETA‐selective antagonists. To date, ETA‐selective receptor antagonists have not been approved to treat kidney disease, despite demonstrating the potential to reduce various nephrotoxic effects.
SC0062 is a highly potent and selective antagonist of ETA that may provide a superior safety profile than nonselective endothelin receptor antagonists. Additionally, the ETA antagonist effects of SC0062 and its major active metabolite M18 are comparable with IC50 values of 2.28 and 1.58 nM, respectively. Although SC0062 is less potent than the ETA selective antagonist atrasentan (IC50, 0.0844 nM), SC0062 and M18 were each more selective for than atrasentan, with notable nephroprotection (Biocity Biopharmaceutics, data on file). This higher selectivity may confer a higher therapeutic index for SC0062. Furthermore, after integrating the human plasma protein binding data of SC0062 and M18 (Biocity Biopharmaceutics, data on file), the free drugs of SC0062 and M18 at the 20 mg dose level were nearly above the IC50 of ETA throughout the entire dosing interval at steady state, with the unbound C min,ss values of SC0062 and M18 being 2.23 and 9.71 nM, respectively. This means that SC0062 may be effective at doses of 20 mg or even lower from the perspective of mechanism of action.
In this FIH trial, single oral doses of SC0062 ranging from 10 to 100 mg and multiple oral doses of 20 or 50 mg daily for 6 days were well tolerated. There were no severe nor serious AEs and a maximum tolerated dose was not observed. Additionally, SC0062 was rapidly absorbed regardless of whether it was administered after fasting or a high‐fat meal.
In both SAD and MAD studies, neither the incidence nor severity of AEs differed between the SC0062 and placebo groups. Transient mild headache was the most common AE. Although headache was experienced erratically and a relationship between headache and dose was not evident in the SAD study, 2 (20%) and 8 (80%) of 10 total subjects experienced headache during 6 days of treatment with SC0062 doses of 20 and 50 mg, respectively, in the MAD study. Headache, head discomfort, neck pain, nasal obstruction, epistaxis, and warm sensations are likely due to the known vasodilative effects of ETA antagonists. These AEs, particularly headache, which was always brief and mild to moderate in severity, has also been the most common AE noted with other ETA inhibitors. 13 In the case of atrasentan, severe headache resulted in treatment discontinuation, precluded dose escalation in its MAD study, and was the most frequent AE reported in another trial. 14 , 15 Hepatotoxicity, characterized by transient transaminase elevations following treatment with ETA antagonists, 16 was not observed with SC0062 in the present study. The numbers of subjects treated at biologically relevant doses of SC0062 for prolonged periods in the SAD and MAD studies are small and cross‐study comparisons should be done with caution. However, preclinical data indicate that in contrast to other ETA antagonists, SC0062 is a weak inhibitor of the bile salt export pump, which may be responsible for the lack of hepatotoxicity observed. 17 The bile salt export pump (BSEP, ABCB11) is the primary transporter of bile acids from the hepatocyte to the biliary system. This rate‐limiting step in bile formation is essential for the formation of bile salt‐dependent bile flow, enterohepatic circulation of bile acids, and digestion of dietary fats. In the FE study, although the C max values of SC0062 and M18 differed between the fasted and fed groups, the AUC values were similar, the incidence and severity of AEs were comparable, and there were no appreciable safety concerns under fasting or fed conditions. No edema, anemia, or weight gain were observed, suggesting that there may be a beneficial safety profile in patients with PAH or CKD.
SC0062 did not exhibit linear PK, with less than proportionate increases in C max, and AUC values with increasing doses from 10 to 100 mg. However, the degree of disproportionality was small as supported by the slopes of PK parameters reflecting exposure for both SC0062 and M18. Additionally, geometric mean CL/F values were similar – 4.53 (1.06) and 5.36 (1.29) L/h at doses of 10 and 100 mg, respectively. Accumulation of SC0062 after 6 days in the MAD study was unremarkable as demonstrated by relatively constant C max and AUC values, whereas a comparable analysis for the active metabolite M18 demonstrated only minor accumulation. In the FIH study of atrasentan, which is in the same chemical class as SC0062, 15 drug exposure also increased less than proportionately when dose was increased 100‐fold from 0.2 to 20 mg, with C max values and AUCtau values increasing from 0.5 to 58.1 ng/mL and 8.8 to 660 ng/mL*h, respectively. At the 20 mg dose level, however, PK parameters reflecting atrasentan exposure were approximately 10‐fold lower than that of SC0062, not accounting for the additional exposure provided by the active metabolite M18. Despite such, and likely due to differences in safety and tolerance, phase II studies of atrasentan in CKD evaluated much lower daily doses (0.75–1.25 mg) than an ongoing study of SC0062 (5–20 mg) in CKD. 18 Additionally, AUEC0–24h values for plasma ET‐1 were 1.58‐fold (0.77–3.20) and 1.83‐fold (1.13–3.63) higher on day 6 from pre‐treatment at the 20 and 50 mg dose levels compared with those receiving placebo, possibly reflecting target engagement and inhibition of ligand binding and/or displacement of ligand by SC0062. Comparable values for ET‐1 following treatment with 20 mg atrasentan in the MAD study were lower overall, averaging 1.34‐fold (1.05–1.49).
The preliminary effects of food on the PK of SC0062 and M18 were evaluated in the FE study. As the geomean t 1/2 values of SC0062 and M18 in the SAD study were 7.25 and 13.73 h, respectively. Additionally, nearly all the plasma concentrations of SC0062 and M18 were less than one‐tenth of the C max at 96 h in the SAD study. These factors supported a washout period of 96 h in the FE study. Administration of SC0062 in the fed state did not meaningfully affect exposure to either SC0062 or M18. However, administration after eating was associated with moderate increases in C max values of SC0062 and M18 by 40.98% and 31.67%, respectively, and prolongation of the SC0062 T max by 3 h, on median, whereas T max values for M18 were unaffected. Although these results suggest that food may delay SC0062 absorption and result in moderately higher C max, albeit with no effects on exposure to SC0062 and M18, an understanding of the exposure–response relationships is required to more fully interpret these results. 19 , 20
In conclusion, these preliminary safety, PK, PD, and FE results in healthy subjects provide a foundation for the administration of SC0062 in relevant disease‐directed studies. Single doses up to 100 mg and multiple doses of 20 and 50 mg of SC0062 were well tolerated and the PK characteristics of SC0062 support a once‐daily dosing schedule. Although eating prior to SC0062 treatment did not affect exposure to either SC0062 or M18 and food restriction is not likely necessary, the relevance of the effects of food on C max and T max should be further evaluated. Overall, these clinical and PK/PD data support further evaluation of SC0062 in CKD, PAH, and other mechanism‐based indications with notable pathology in the ET axis.
AUTHOR CONTRIBUTIONS
Y.L., C.Y., J.J., and S.W. designed the study. Y.L, W.W., H.Q., Y.G., Y.W., R.S., and Q.C. performed the research. X.L. and L.Z. analyzed the data. All authors wrote the manuscript.
FUNDING INFORMATION
This study was sponsored by Biocity Biopharmaceutics Co., Ltd.
CONFLICT OF INTEREST STATEMENT
E.R., S.W., X.L., K.G., B.Z., W.Z., and L.Z. are employees of Biocity Biopharmaceutics Co., Ltd, Wuxi, China. All other authors declared that each has no competing interests with the subject of the article.
Supporting information
Appendix S1.
ACKNOWLEDGMENTS
The authors would like to thank the volunteers who took part in the trial, as well as the staff of the Phase I Clinical Research and Quality Consistency Center for the Evaluation for Drugs (Shanghai, China).
Liu Y, Wang W, Qian H, et al. Safety, pharmacokinetics, and pharmacodynamics in healthy Chinese volunteers treated with SC0062, a highly selective endothelin‐A receptor antagonist. Clin Transl Sci. 2024;17:e13750. doi: 10.1111/cts.13750
Yun Liu and Wei Wang contributed equally to this article.
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Supplementary Materials
Appendix S1.