1 Introduction
Influenza remains an ever-present threat worldwide, with the potential to cause a pandemic. Seasonal epidemics result in substantial morbidity and mortality, leading to healthcare expenses and economic losses due to work absenteeism. By 2022, around a billion people are affected by influenza annually, with 3 to 5 million severe cases and 290 000 to 650 000 deaths [
1]. Vulnerable populations, such as the elderly and young individuals, are at a higher risk of experiencing severe complications from influenza [
2]. Although vaccination and nonpharmaceutical interventions help mitigate the burden of influenza infections to some extent, antiviral therapies play a critical role in treating acutely ill patients and managing outbreaks.
Until 2018, available antiviral treatments for influenza included neuraminidase inhibitors (such as oseltamivir, zanamivir, peramivir), M2-inhibitors (adamantanes), a viral RNA synthesis inhibitor (ribavirin), and a polymerase inhibitor (favipiravir) [
3]. Among these drugs, oseltamivir was the most widely used for influenza treatment. Several published articles demonstrated that oseltamivir accelerated the alleviation of clinical symptoms, and reduced the risk of lower respiratory tract complications and hospital admissions [
4–
6]. However, its effectiveness in “at-risk” groups is limited. Resistant strains were identified in 2%–8% of young children treated with oseltamivir [
7]. Resistant A/H3N2 strains emerged during prolonged courses of oseltamivir in immunosuppressed individuals [
8]. The management of drug-resistant influenza virus infections is challenging and usually requires combination treatments. In 2018, baloxavir marboxil was licensed in Japan for the treatment of influenza A and B viruses. When metabolized into its active form, baloxavir acid, it functions as a novel cap-dependent endonuclease (CEN) inhibitor.
In vitro experiments indicated that baloxavir exhibited broad potency against various subtypes of influenza A and B viruses (such as H1N2, H5N1, H5N2, H5N6, H7N9, H9N2), including oseltamivir-resistant strains [
9]. Among patients with uncomplicated influenza, single-dose baloxavir was superior to placebo in alleviating influenza symptoms, and superior to both oseltamivir and placebo in reducing the viral load 1 day after initiation of the trial (CAPSTONE-1) [
10]. Among patients at high risk of influenza complications, baloxavir also accelerated clinical recovery and reduced complications (CAPSTONE-2) [
11]. So far, baloxavir marboxil is the only approved CEN inhibitor in clinical practice. However, due to limitations in terms of price and accessibility, it is still not widely available for patients with acute influenza in China.
ADC189, a deuterated form of baloxavir marboxil, is also a CEN inhibitor. It undergoes rapid conversion into active metabolites, specifically ADC189-I07, which directly binds to divalent metal ions in PA subunit, then restrains CEN activity and finally inhibits viral RNA transcription. The objective of the current study is to describe the in vitro characterization of ADC189 and the in vivo efficacy (anti-viral activity) to support its potential for clinical application. Other nonclinical studies (not presented here) have included toxicology studies of up to 28 days duration in Sprague-Dawley rats and 28 days duration in cynomolgus monkeys and demonstrated that ADC189 showed little evidence of toxicity. Moreover, we evaluated the safety, tolerability, and pharmacokinetic (PK) profiles of ADC189 in healthy volunteers. Furthermore, we investigated the food effect on ADC189. These assessments aided in the selection of appropriate dosages for the phase 2 study.
2 Materials and methods
2.1 Luciferase reporter assay
HEK293T/17 cells were plated at a density of 60 000 cells per well in a 96-well cell culture plate and incubated overnight at 37 °C with 5% CO2. On the following day, the constructed influenza virus polymerase reporter plasmids (constructed by GENEWIZ, New Jersey, USA), including influenza virus PA (wild-type or I38T mutant strain), PB1, PB2, NP, and the reporter gene pGL2-luciferase plasmid, were transfected into the cells using TransIT-293 (Mirus, GA, USA). Each well was transfected with 90 ng of influenza virus PA, PB1, PB2, NP, and the pGL2-luciferase plasmid, along with 20 ng of pRenilla luciferase (Promega, Wisconsin, USA) as control. A group without the PA plasmid was set as the 100% efficacy control. After 6 h of transfection, the supernatant was removed, and cell culture medium containing compounds (3-fold serial dilutions, 8 concentration points, triplicate wells) was added. The final concentration of DMSO in the cell culture medium was 0.5%. The cells were then incubated for 24 h at 37 °C with 5% CO2. Dual-luciferase reporter assay system (Promega, Wisconsin, USA) was used to detect intracellular luciferase expression. The relative luciferase values (Firefly/Renilla) were calculated to determine the effect of compounds on influenza virus polymerase activity.
2.2 Cytopathic effect (CPE) inhibition assay
MDCK cells seeded in 96-well plates at a density of 15 000 cells per well were infected with the specific viruses and cultured in medium containing both the compound and virus. Cell viability was assessed after 5 days (the proportion of damaged cells in the virus infection control wells without any compounds ranged from 80% to 95%) using a CCK-8 proliferation assay kit (Life iLab, Shanghai, China). The 50% cytotoxicity concentration (CC50) of the compound was assessed in the absence of the viruses.
2.3 Plaque reduction assay
MDCK cells seeded in 96-well plates were infected with approximately 50 PFU/well of test strains. Following incubation at 35 °C in a CO2 incubator for 1 h, the cells were overlaid with virus assay medium containing the test substances. After incubation for 22 h at 35 °C, the cells were fixed and treated with primary antibody (MAB8257, MAB8258, and MAB8258, Millipore, MA, USA) and secondary antibody (5220-0341, KPL, MA, USA), subsequently. ELiSPOT was used to read the raw data.
2.4 In vivo analysis
To study the anti-viral effect of ADC189 in mice, a total of 18 7-week-old female BALB/c mice were used in each preventive group. The mice were anesthetized with zoletil 50/xylazine and intranasally inoculated with 4500 PFU of A/WSN/33 (H1N1) in a volume of 50 μL. The mice were orally administered with solvent, oseltamivir phosphate (5 mpk), ADC189 (0.5 mpk), ADC189 (1.5 mpk), or ADC189 (5 mpk) by gavage for a duration of 7 days, twice daily at intervals of 8/16 h. The initial administration took place 2 h prior to viral inoculation. On day 5 (with the inoculation day considered as day 0), eight mice from each group were euthanized, and their lungs were collected for virus titer analysis using plaque reduction assay. The remaining mice (n = 10) were monitored for a period of 14 days to assess weight loss and mortality.
In a separate treatment experiment, 18 7-week-old female BALB/c mice were used in each group. The mice were anesthetized with zoletil 50/xylazine and intranasally inoculated with a 50 μL volume of 1000 PFU of A/WSN/33 (H1N1). The mice were administered with solvent, oseltamivir phosphate (10 mpk), ADC189 (0.2 mpk), ADC189 (1 mpk), or ADC189 (10 mpk) by gavage for 7 days, twice daily at intervals of 8/16 h. The initial administration took place 48 h after the viral inoculation. On day 5 (day 0 as the inoculation day), eight mice from each group were euthanized, and their lungs were collected for virus titer analysis. The remaining mice (n = 10) were monitored for 14 days to observe weight loss and mortality. A humanitarian endpoint was established according to the Institutional Animal Care and Use Committee protocol. If any mouse experienced a weight loss exceeding 35% compared to its baseline weight on day 0, or/and displayed moribund signs, it would be euthanized. Such cases were recorded as deceased animals in the results. The virus titer in the sample was expressed as log10(plaque numbers per gram of lung tissue sample) = log10 (plaque numbers per well × dilution factor × 1000).
2.5 Subjects
Subjects were recruited through recruitment advertisements. A total of 354 healthy subjects from various communities in China underwent screening, with 338 subjects assigned to the single ascending dose (SAD) arm and 16 subjects assigned to the food effect (FE) arm. The eligible population consisted of healthy Chinese males weighing ≥ 50 kg and females weighing ≥ 45 kg, aged between 18 and 55 years, with a body mass index ranging from 19 to 26 kg/m2, and without any clinically significant medical conditions. All subjects provided written informed consent prior to enrollment. The complete set of inclusion and exclusion criteria are listed in Table S1.
2.6 Study treatment and design
This phase I, randomized, placebo-controlled, single-center, double-blind study comprised a SAD analysis and a FE analysis. To maintain the blinding, neither the subjects, researchers, monitors, nor data analysts were aware of the drug dispensation. The placebo used in the study was designed to resemble the trial drug in terms of shape, taste, and weight. The enrollment of this trial was between March 15, 2022 to November 6, 2022.
2.6.1 SAD design
The starting dose of 15 mg for the SAD study was based around a maximum recommended starting dose (MRSD) approach (with conversion for body surface area) as proposed in FDA guidance “Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers” (FDA, 2005) using the No Observed Adverse Effect Level (NOAEL) from toxicology studies in the most sensitive species which was rat (15 mg/kg/day). Thus, 15 mg/kg / 6.2 body surface area / 10-fold safety factor × 60 mg person give a MRSD of 15 mg. The highest dose in the SAD study was set at 90 mg, which is in reference to the dose used in the first-in-human trial of baloxavir marboxil (80 mg) [
12] and the drug formulation specification (15 mg/tablet). ADC189 was tested in a total of six dose groups: 15, 30, 45, 60, 75 and 90 mg. Four subjects were included in 15 mg group, with three receiving the trial drug, and one receiving a placebo (3:1 randomization). The other five dose groups had eight subjects each, with 6 receiving the trial drug, and 2 receiving a placebo (6:2 randomization). The next dose was administered after confirming the safety of the prior dose.
The research process encompassed several stages, including screening, a baseline period (day –28 to day –1), an administration period (day 1 to day 4), and a follow-up period (day 6 to day 15). All 338 subjects were assessed for eligibility at the initial screening visit, and 47 subjects eligible for the formal trial were admitted to the clinical site for further baseline assessments at day –1. Eligible subjects were administered a single oral dose of ADC189 or placebo on day 1, after fasting for 10 h before administration and continuing for 4 h after administration. After the administration, the observation lasted until the morning of day 4 (72 h after administration). During this period, subjects underwent safety assessments, including vital signs, physical examination, clinical laboratory testing, and ECG. PK plasma collection was also performed at this period. Subjects were discharged from the clinic on the morning of day 4 and returned to the clinical site for a follow-up review at day 6, day 8, and day 15 after administration.
2.6.2 FE design
This study was designed as a single-center, randomized, two-cycle, two-crossover study to access the effects of food on the PK and safety of ADC189 in healthy adults. A total of 16 subjects were randomly divided into two equal groups: A and B. At cycle 1, the subjects in the cohort A received a 45 mg oral dose of ADC189 under fasted and the subjects in the cohort B received a 45 mg oral dose of ADC189 after consuming a standardized meal. Subjects underwent safety assessments and PK plasma collection at day 4, and received follow-up review at day 6, day 8, and day 15 after administration. The washout period lasted for 21 days. On day 22, subjects entered the cycle 2 of crossover dosing (the subjects in the cohort A received a 45 mg oral dose of ADC189 after consuming a standardized meal and the subjects in the group B received a 45 mg oral dose of ADC189 under fasted).
2.7 Assessment and analysis
2.7.1 Analysis population
Full analysis set (FAS) included all enrolled subjects who received randomization and was used to analyze subject dropout, as well as demographic data and baseline characteristics. Safety set (SS) included all enrolled subjects who received randomization and at least one dose of the investigational drug. PK concentration set (PKCS) including all enrolled subjects who received randomization and at least one dose of the investigational drug, and have at least one observed PK concentration data, was used for the PK concentration analysis. PK parameter set (PKPS) including all enrolled subjects who received randomization and at least one dose of the investigational drug, without significant deviations affecting PK evaluation parameters, and received at least one PK parameter data, was used for reliably estimating the PK parameters. Food effect set (FES) including all enrolled subjects who received randomization and used the investigational drug, completed at least one cycle of the food effect study, and had at least one PK parameter without significant deviations affecting PK evaluation parameters, was used for the food effect analysis.
2.7.2 Safety assessments
Safety assessments included adverse events, clinical vital signs, physical examinations, laboratory testing, and ECG. All adverse events (AEs) will be encoded using Medical Dictionary for Regulatory Activities (version 25.0), and the occurrences of AEs in subjects will be summarized by System Organ Class (SOC), Preferred Term (PT), and dose group. The summary will include the number of subjects (n), number of occurrences, and percentage (%). AEs were graded according to Common Terminology Criteria for Adverse Events (v5.0).
2.7.3 Pharmacokinetic assessments and analysis
Blood samples for pharmacokinetic analyses were obtained 1 h before and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 120, 168, 336 h after ADC189 administration. Plasma concentrations of ADC189 and its reactive metabolite, ADC189-I07, were determined using validated liquid chromatography-tandem mass spectrometry methods. Pharmacokinetic parameters analyzed included maximum observed plasma concentration (Cmax), time to maximum observed plasma concentration (Tmax), area under curve from 0 to last measurable concentration (AUC0–t), total AUC from time 0 to infinity (AUC0–inf), terminal elimination half-life (T1/2), terminal elimination rate (λz), total clearance (CL), volume of distribution (Vz), mean residence time (MRT), apparent clearance (CL/F) where F is the fraction of the dose absorbed, apparent volume of distribution (Vz/F), plasma concentration at 24 h after administration (C24), plasma concentration at 48 h after administration (C48), plasma concentration at 72 h after administration (C72). Power model was used to explore the proportional relationship between key pharmacokinetic parameters (AUC0–t, AUC0–inf, Cmax, C24, C48, C72) and dose.
2.7.4 Food effect assessment
The impact of food on the pharmacokinetics of ADC189 active metabolites, specifically ADC189-I07, was assessed in the FES. Calculations were performed using SAS 9.4. The parameters of interest included the geometric mean ratios (fed/fasted) with 90% confidence intervals for Cmax, AUC0–t, and AUC0–inf.
2.8 Statistical analysis
In the preclinical part of the study, statistical analysis was performed using GraphPad Prism (version 5, GraphPad Software, Inc, USA). All data were expressed as mean ± SD. In the luciferase reporter assay, CPE inhibition assay, and plaque reduction assay, the EC50 values were determined through nonlinear regression analysis. One-way ANOVA was used to determine statistical differences in viral titers in lung tissues, while two-way ANOVA was employed to analyze body weight changes. Survival analysis was conducted using the log-rank (Mantel-Cox) test.
In the phase I study, all descriptive statistical analyses were performed using SAS (USA, v9.4 or later). The sample size was not determined through statistical power calculation and was based on the guideline of NMPA (National Medical Products Administration). Pharmacokinetic parameters were calculated by non-compartmental analysis using Phoenix WinNonlin (Certara, v8.31 or later). A mixed-effects model was employed to assess the dose-proportionality of ADC189 and the impact of food on pharmacokinetics.
3 Results
3.1 Inhibition of polymerase activity by ADC189
The active metabolite of ADC189 is ADC189-I07. A dual-luciferase reporter assay was performed to investigate the inhibitory activity of the test compounds (ADC189-I07) against the polymerase of influenza virus A/WSN/33 (H1N1) wild type and PA I38T mutant strain. Baloxavir, a PA endonuclease inhibitor and oseltamivir acid, a NA inhibitor, were employed as positive and negative control compounds, respectively. Oseltamivir acid did not exhibit any anti-polymerase activity within the tested concentrations, with an EC50 value exceeding the maximum detection limit (> 100 μmol/L). ADC189-I07 and baloxavir demonstrated significant inhibitory activity against the wild-type polymerase, with EC50 values of 2.52 nmol/L and 2.22 nmol/L, respectively. When tested against the PA I38T mutant strain polymerase, both ADC189-I07 and baloxavir exhibited reduced activity compared to the wild type, with EC50 values of 173 nmol/L and 159.8 nmol/L, and fold-shifts of 68.79 and 72.05, respectively (Tab.1). These findings indicate that ADC189-I07 possesses inhibitory activity against both wild-type and PA I38T mutant strain polymerases, with comparable inhibitory activity to baloxavir.
3.2 Potent and broad activities of ADC189
To evaluate the antiviral potency of ADC189-I07 in infected cells and compare it with baloxavir, a CPE inhibition assay was performed using 10 laboratory strains obtained from American Type Culture Collection (ATCC), which included 8 influenza A viruses and 2 influenza B viruses. ADC189-I07 showed great potency against influenza A and B viruses, with mean EC50 values ranging from 0.24 to 12.25 nmol/L, exhibiting a similar antiviral capacity to baloxavir. Furthermore, the inhibitory effects of ADC189-I07 against various clinically isolated strains of influenza viruses, including H1N1, H3N2, and influenza B, were evaluated. ADC189-I07 displayed high potency against these strains, with mean EC50 values ranging from 0.67 to 1.30 nmol/L, 0.45 to 0.47 nmol/L, and 5.11 to 5.38 nmol/L, respectively (Tab.2).
3.3 Antiviral efficacy of ADC189 in mice
The anti-viral efficacy of ADC189 was evaluated in H1N1-infected mice. In the preventive groups, mice treated with the solvent control exhibited a rapid weight loss of approximately 11% by day 3. However, both oseltamivir phosphate and ADC189 administration prevented weight loss (Fig.1). By day 7, the solvent-treated mice began to succumb to the infection, and all of them had died by day 10. In contrast, all mice in the oseltamivir and ADC189 treatment groups remained alive till the end of the experiment (Fig.1). Additionally, at the designated dosage, the viral titers in the ADC189 treatment groups reached the detection limit of 3.00 log10(plaque numbers/g lung), which was much lower than those in the solvent and oseltamivir treatment groups (7.03 log10(plaque numbers/g lung) and 5.29 log10(plaque numbers/g lung), respectively; P < 0.0001; Fig.1). These results demonstrate that ADC189 exhibits robust protective efficacy when used as preventive medication for influenza virus infection, even at a low dosage.
In the treatment groups, mice in the solvent group and the ADC189 (0.2 mpk) treatment group experienced a significant decrease in body weight by day 3, which continued to decline until death. However, administration of 1 mpk and 10 mpk doses of ADC189 effectively alleviated weight loss (Fig.1). Meanwhile, mice treated with 1 mpk and 10 mpk doses of ADC189 showed a longer median survival time compared to the solvent group and the oseltamivir treatment group (1 mpk-ADC189, 13 days; 10 mpk-ADC189, 10 days; solvent, 6 days; and oseltamivir, 7.5 days; Fig.1). Moreover, the average viral titer in the solvent group was 6.82 log10(plaque numbers/g lung). In comparison, the average viral titers in mice treated with 0.2 mpk, 1 mpk, and 10 mpk doses of ADC189 decreased by 1.88 log10(plaque numbers/g lung), 2.19 log10(plaque numbers/g lung), and 2.64 log10(plaque numbers/g lung), respectively (P < 0.0001; Fig.1). These results indicate that medium and high doses of ADC189 gained favorable therapeutic efficacy in vivo, and exhibited a certain degree of dose-dependent response.
3.4 Subject disposition
In SAD study, a total of 47 subjects were enrolled and randomized to receive different doses of ADC189: 15 mg (n = 3), 30 mg (n = 6), 45 mg (n = 6), 60 mg (n = 7), 75 mg (n = 6), 90 mg (n = 6), as well as a placebo group (n = 13, Fig.2). The median age of all participants was 29 years (range, 18–45 years). The majority of the subjects (74.5%) were male. The mean body weight was 61.35 kg (range, 46.6–80.5 kg), the mean height was 167.25 cm (range, 149.0–181.5 cm) and the mean body mass index (BMI) was 22.15 kg/m2 (range, 19.1–25.6 kg/ m2, Tab.3). Ultimately, 43 volunteers completed the study, with 2 cases in the placebo group and 1 in the ADC189 60 mg group not receiving the drugs.
In the FE study, 16 subjects were randomized and received drugs, with 8 participants in the fasted-fed cohort and 8 participants in the fed-fasted cohort, respectively. Among the participants, 75% were male, with a mean age of 28 years (range, 18–40 years), a mean body weight of 61.95 kg (range, 51.4–75.4 kg), a mean height of 168.25 cm (range, 157.5–179.5 cm) and a mean BMI of 21.75 kg/m2 (range, 20.1–25.1 kg/ m2, Tab.3).
3.5 Pharmacokinetics
A total of 33 subjects were included in the pharmacokinetics analysis in the SAD part of the study. Generally, the mean Cmax values increased in a dose-dependent manner across the entire dose range of 15–90 mg. With a 6-fold increase in dose, Cmax increased 10-fold. The time to reach the peak ADC189-I07 plasma concentration (Tmax) and the total exposure to ADC189-I07 (area under the curve, AUC) were similar between the 30 mg and 45 mg dose groups, as well as between the 60 mg and 75 mg dose groups. The clearance of ADC189-I07 was similar across all dose groups, showing a gradual decline over 72 to 96 h, with terminal elimination half-life (T1/2) ranging from 76.69 to 98.28 h (Fig.3, Tab.4).
In the FE part of the study, 16 participants underwent pharmacokinetics analysis. After consuming a standardized meal, the Cmax was slightly decreased compared to the fasting state (93.58 in fasting subjects, 89.51 in the fed state). However, there was no significant difference in the Tmax, AUC, and T1/2 between the fed and fasting states. The mixed effect model analysis confirmed that food had no significant effect on the concentration, clearance, and exposure of ADC189-I07 (Fig.3, Tab.5).
3.6 Safety and tolerability
In SAD analysis, a total of 32 subjects (72.7%) reported a combined total of 46 TEAEs, including 10 cases (90.9%) in placebo group (17 AEs), 2 (66.7%) in 15 mg group (3 AEs), 2 (33.3%) in 30 mg group (2 AEs), 4 (66.7%) in 45 mg group (7 AEs), 6 (100%) in 60 mg group (8 AEs), 4 (66.7%) in 75 mg group (4 AEs), and 4 (66.7%) in 90 mg group (5 AEs). No serious adverse events (SAEs) were reported during the study, and only one subject in the 90 mg group withdrew from the trial due to a mental disorder. The incidence or intensity of TEAE did not show any correlation with the dose of ADC189.
In the FE part, a total of 26 TEAEs were observed in 11 (87.5%) fasted subjects, while 23 TEAEs were observed in 9 (60.0%) fed subjects. All participants in this part of the study completed the trial without experiencing any SAEs or AEs that led to withdrawal.
The most common adverse events reported were hypotension (16.2%), increased levels of serum total bilirubin (11.8%), and elevated white blood cell count (10.3%). Among the reported AEs, 88.4% resolved before the end of the study. No notable trends were identified in terms of changes from baseline or increase in abnormalities for clinical laboratory tests, vital signs, or ECG assessments (Tab.6).
4 Discussion
This study represents the first evaluation of ADC189, a cap-dependent endonuclease inhibitor used in antiviral treatment, in both pre-clinical and clinical settings. The study aimed to assess the efficacy in vitro and in vivo, pharmacokinetics, and safety of ADC189 in healthy Chinese volunteers. The preclinical results revealed that ADC189 exhibited high potency and demonstrated broad-spectrum coverage against various types of influenza viruses. When utilized for influenza virus infection, ADC189 demonstrates a strong protective efficacy in mice. Besides, administration of a single dose of ADC189 was safe and well-tolerated in healthy volunteers. All AEs reported were mild, and no SAEs were documented. After single-dose oral administration, ADC189 was rapidly metabolized into ADC189-I07. The pharmacokinetics of ADC189-I07 showed that its exposure increased in a dose-dependent manner over the entire dose range of 15 to 90 mg, and exhibited a long elimination half-life. Importantly, the study also determined that food intake did not have any significant impact on the concentration, clearance, or exposure of ADC189.
In the luciferase reporter analysis, ADC189-I07 exhibited similar inhibitory activity to baloxavir, suggesting that ADC189 has an inhibitory effect on the influenza virus polymerase. Besides, amino acid substitutions in the PA protein could reduce the susceptibility of the virus to baloxavir. Specifically, the PA I38T mutant strain, which involves a threonine (T) substitution for serine at position 38, exhibited the greatest reduction in susceptibility to baloxavir, with a 27–57 times change in EC50
in vitro [
13]. In this study, we found that both ADC189-I07 and baloxavir showed decreased activity against the PA I38T mutant strain polymerase compared to the wild type. Their respective EC50 values were 173 nmol/L and 159.8 nmol/L, with fold-shifts of 68.79 and 72.05, indicating that ADC189 also targets the influenza virus endonuclease and exhibits satisfying antiviral efficacy comparable to baloxavir.
In the in vitro activity test of influenza virus A/WSN/33 (H1N1), the average synergistic index and antagonistic index of ADC189-I07 combined with oseltamivir were 327.14 and −11.52, respectively (data not presented here), suggesting a highly synergistic effect.
These experimental results support the combined application of ADC189 and oseltamivir for the treatment of patients with highly pathogenic avian influenza and sever influenza.
In the current study, the mean value of C24 for ADC189 at a dosage of 15 mg was 9.59 ng/mL, which corresponds to approximately 40.5%–52.8% of the C
max, indicating that ADC189 can provide superior inhibition of virus replication compared to oseltamivir (C24 ≥ 6.85 ng/mL) [
12]. The mean half-life (T
1/2) was observed to be 90.2 h for the 75 mg dosing group, and 83.6 h for the 45 mg dosing group. These values are comparable to that reported in another study of baloxavir marboxil conducted in the Chinese population (80 mg group, 88.9 h; 40 mg group, 99.7 h) [
14]. These findings suggest that ADC189 could be taken as a single-dose oral medication to cure influenza just like baloxavir marboxil. Besides, the mean C
max and AUC
0–inf were 1.7 and 1.8 times higher in subjects who received 75 mg of ADC189 compared to those who received 45 mg of ADC189. Similar dose–response relationships have been observed in various studies of baloxavir marboxil conducted in Chinese and Japanese individuals [
12,
15,
16]. Previous studies have reported that body weight is relevant in the metabolism and clearance of baloxavir. In our study, we also found that C
max, AUC
0–t, and C24 decreased with increasing body weight. Moreover, a tendency of lower baloxavir acid exposure was observed when baloxavir marboxil was taken with food [
17,
18]. However, our data indicate that ADC189 may be taken with or without food.
Participants enrolled in our study who received single oral doses of ADC189 experienced very few TEAEs overall, and no SAEs or deaths were reported. Only one subject who received a 90 mg dose of ADC189 in the SAD part of the study withdrew due to a mental disorder, which was mild in severity and resolved without any treatment. Also, there was no correlation observed between TEAEs, including their incidence or severity, and the dose of the drug or food consumption. Overall, there were no clinically significant changes in vital signs or safety laboratory tests at any of the tested doses.
In conclusion, this study demonstrated that ADC189, a novel CEN inhibitor, exhibited potent and broad activities against various types of influenza viruses. Its efficacy was found to be superior to oseltamivir and comparable to baloxavir marboxil. In the phase I study, single-dose oral administration of ADC189 was generally safe and well-tolerated, with favorable pharmacokinetic characteristics. It demonstrated an excellent antiviral efficacy and a notable long half-life in healthy Chinese volunteers, supporting the feasibility of single oral dosing. Overall, the promising results from the clinical development of ADC189 as a novel treatment option for acute influenza indicate ongoing progress in its potential as an effective therapeutic approach.
PDF
(2270KB)
