3.1 Participants3.1.1 Study 1: Age and Sex

A total of 57 participants received study treatment and completed the study (Table S3). Data from all participants were included in safety, pharmacokinetics and pharmacodynamics analyses. Demographic characteristics (besides age) were comparable between the groups.

3.1.2 Study 2: Renal Impairment

A total of 48 participants received treatment: eight each in both the matched-control groups with normal kidney function, eGFR G2, G3 and G4 groups, and the dialysis groups (Table S3). Data from all participants were included in the safety analysis. One participant with eGFR G4 did not complete the study; hence, only 47 participants were included for pharmacokinetics and pharmacodynamics analysis. Other demographic characteristics (besides age) were comparable between the groups.

3.1.3 Study 3: Liver Impairment

A total of 26 participants received treatment and completed the study; nine each in the matched-control and mild liver impairment groups and eight in the moderate liver impairment group (Table S3). Data from all participants were valid in safety, pharmacokinetics and pharmacodynamics analysis. Demographic characteristics were comparable between the groups.

3.2 Safety and Tolerability

The incidence of all treatment-emergent AEs (TEAEs) by primary system organ class and preferred term is presented in Table S4.

3.2.1 Study 1: Age and Sex

Overall, asundexian 25 mg had a good safety profile and was well tolerated across all age and sex groups. All TEAEs were of mild intensity and were reported as having resolved at the end of the study. No deaths or treatment-emergent serious AEs (SAEs) occurred during the study. There were no study drug-related bleeding events or TEAEs of special interest.

Of 57 participants, 12 (21.1%) experienced at least one TEAE. Predominant TEAEs belonged to the primary system organ classes “gastrointestinal disorders” (five participants [8.8%]), “musculoskeletal and connective tissue disorders” (three participants [5.3%]) and “nervous system disorders” (three participants [5.3%]).

The most frequently documented TEAEs were back pain (three participants [5.3%] in total; two “young” females and one “old” male, all treated with asundexian) and headache (three participants [5.3%] in total; one “young” female, one “elderly” female and one “old” male, all treated with asundexian).

3.2.2 Study 2: Chronic Kidney Disease (eGFR G2, G3 and G4)

In general, asundexian 25 mg had a good safety profile and was well tolerated across all kidney function groups. Two treatment-emergent SAEs were reported in one participant in the eGFR G4 group (accident and traumatic fracture, both severe) in addition to a third TEAE (mild skin laceration). The accident (reported as accidental fall) and traumatic fracture (reported as traumatic right femur fracture), required hospitalisation. The skin laceration was treated with a bandage. None of these three TEAEs were considered drug-related by the investigator.

Overall, three participants (9.4%) experienced six TEAEs: gingivitis, accident, skin laceration, traumatic fracture, increased C-reactive protein and headache (3.1% each) (Table S4). With the exception of the TEAEs related to the accident, all were mild and resolved by the end of the study. The TEAE headache was judged to be related to the study drug by the investigator. There were no study drug-related bleeding events or TEAEs of special safety interest.

3.2.3 Study 2: End-Stage Kidney Disease on Dialysis

Overall, two participants (12.5%) experienced one TEAE each in Part B: increased amylase (6.3%) and increased glutamate dehydrogenase (6.3%) (Table S4). Both TEAEs occurred in the ESKD group on the dialysis-free day and were not observed on the dialysis day. Both TEAEs were mild, self-limiting and judged as not drug-related by the investigator. There were no unprovoked drug-related bleeding events or TEAEs of special interest.

3.2.4 Study 3: Liver Impairment

In general, asundexian 25 mg had a good safety profile and was well tolerated across all liver function groups. Two TEAEs were reported, both of mild intensity and reported as resolved at the end of the study. No deaths or treatment-emergent SAEs occurred during the study. There were no study drug-related bleeding events or TEAEs of special safety interest.

Two participants (7.7%) in the moderate liver impairment group reported one TEAE each, of mild intensity. One TEAE headache was observed on dosing day, 40 min post-dose, treated with a single 500 mg oral dose of metamizole sodium, and resolved during the same day. It was judged as drug related by the investigator. Another participant with a history of intermittently increased amylase values presented increased amylase values throughout the study with a peak at 4 days post-dose at 329 U/L (3.290 × upper limit of normal). No symptoms indicative of pancreatitis were observed. It was not considered to be drug related by the investigator as the participant had a history of increased pancreatic enzymes. The TEAE was resolved 8 days post-dose.

No clinically relevant effects of asundexian on clinical laboratory profiles (besides increased amylase in study 3), vital signs or electrocardiogram readings were observed across all three studies.

3.3 Pharmacokinetics

The effect of intrinsic factors on asundexian exposure is shown in Fig. 1. Mean plasma concentration–time profiles for asundexian for studies 1, 2 and 3 are shown in Fig. 2 and pharmacokinetic parameters are provided in Tables 1, 2 and 3.

Fig. 1

Effect of intrinsic factors on asundexian exposure; data presented as geometric LS means and 90% CIs. AUC area under the plasma concentration–time curve, AUCu area under the unbound plasma concentration versus time curve from zero to infinity after single (first) dose, CI confidence interval, CKD chronic kidney disease, Cmax maximum observed drug concentration in plasma after single-dose administration, Cmax,u maximum unbound drug concentration in plasma after single-dose administration, eGFR estimated glomerular filtration rate, ESKD end-stage kidney disease, LS least squares

Fig. 2

Concentration versus time profiles of asundexian in plasma after single oral-dose administration of asundexian 25 mg in different age and sex groups (study 1) (a); for total asundexian in CKD (study 2, Part A) (b); for total asundexian in ESKD (study 2, Part B) (c); and for total asundexian in participants with liver impairment (study 3) (d). CKD chronic kidney disease, eGFR estimated glomerular filtration rate, ESKD end-stage kidney disease, LLOQ lower limit of quantification

Table 1 Pharmacokinetics parameters for asundexian in study 1Table 2 Pharmacokinetics parameters for total and unbound asundexian in study 2Table 3 Pharmacokinetic parameters for total and unbound asundexian study 33.3.1 Study 1: Age and Sex

Based on the pooled population of male and female participants, the AUC of asundexian increased in “elderly” and “old” participants (by 26% and 29%, respectively) compared to “young” participants, with the most pronounced effect in “old” female participants (37% increase in AUC compared to “young” female participants). In the pooled population, Cmax was not affected by age. However, an increase of 22% in Cmax was observed in “old” female compared to “young” female participants (Fig. 1). Geometric mean t1/2 was not meaningfully affected by age (Fig. 2a and Table 1).

In the pooled population, sex had no relevant effect on AUC and Cmax of asundexian. However, an increase of 20% in AUC and 38% in Cmax was observed when comparing “old” female to “old” male participants (Fig. 1).

3.3.2 Study 2: Chronic Kidney Disease (eGFR G2, G3 and G4); Part A

After a single dose of asundexian 25 mg, median tmax was similar for all kidney function groups. Mean Cmax was 11% and 17% higher in participants in the eGFR G2 and G4 groups, respectively, and 9% lower in those in the eGFR G3 group compared to the normal kidney function group, with 90% CIs including unity. There was no consistent effect on the exposure of asundexian with worsening kidney function according to eGFR category (Figs 1 and 2b). Exposure (AUC) to total asundexian was about 16%, 8% and 39% higher in participants in eGFR G2, G3 and G4 groups, respectively, compared to the respective controls (Fig. 1). Determination of the fu of asundexian revealed a trend for decreasing geometric mean values with worsening kidney function, with 8%, 7%, 6% and 5% for those with normal kidney function and in eGFR G2, G3 and G4 groups, respectively (Table 2). However, the distribution of individual values overlapped substantially (Fig. S4). Subsequently, changes in CLu/F led to a similar AUCu in participants in the eGFR G2 group (+0.3%) and a slightly lower exposure of −21% and −12% in the eGFR G3 and G4 groups, respectively, as compared to those with normal kidney function (Table 2). Similar results have been observed for Cmax,u, which was 3%, 33% and 25% lower in participants in the eGFR G2, G3 and G4 groups, respectively. Median t1/2 was only marginally longer in the eGFR G3 (24.2 h) and G4 groups (23.8 h) compared with the eGFR G2 (20.4 h) and control (19.1 h) groups. The %AE,ur was similar across eGFR category groups, but according to the slight increase in total AUC, CLR was lower in participants with impaired kidney function compared to those with normal kidney function (Table 2).

3.3.3 Study 2: End-Stage Kidney Disease on Dialysis; Part B

On the dialysis-free day, median tmax was slightly lower in participants with ESKD (3.5 h) compared to the matching control group (4.5 h) (Table 2 and Fig. 2c). Determination of fu of asundexian revealed only slightly lower geometric mean values in participants with ESKD (5% on the dialysis-free day) than in the matched-control group with normal kidney function (7%) (Table 2). Subsequently, the effect on AUCu (−40%) and Cmax,u (−37%) was slightly more pronounced than on the exposure to total asundexian (Fig. 1). The t1/2 was nearly not affected, with similar values in both groups (17.3 h for participants with ESKD on their dialysis-free day and 17.7 h for the control group; Table 2). Mean CLR could not be determined in participants with ESKD as only three participants provided urine on their dialysis-free day; on the dialysis day, just one participant provided a sample.

3.3.3.1 Impact of the Dialysis Procedure

In participants with ESKD, maximum plasma concentrations were observed 1.5 h earlier (at 2.0 h) with haemodialysis, which was performed 1 to 5 h after oral administration of asundexian 25 mg, compared to the dialysis-free day (3.5 h) (Table 2 and Fig. 2c). Mean total and unbound exposure to asundexian as well as the fu were not affected by the dialysis procedure (Fig. 1 and Table 2). The point estimates for the ratios of AUC and Cmax were close to unity, with the 90% CIs including unity when comparing total asundexian exposure in participants with ESKD on their dialysis day with their dialysis-free day (Fig. 1).

3.3.4 Study 3: Liver Impairment

Concentration–time curves of asundexian for participants with mild and moderate liver impairment and the group with normal liver function are provided in Fig. 2d, and pharmacokinetic parameters are summarised in Table 3.

Asundexian was absorbed with comparable median tmax values across the groups (Table 3). Mild and moderate liver impairment was not associated with a relevant effect on asundexian exposure (Fig. 1) compared to the normal liver function group. A slightly lower mean of apparent oral clearance and higher volume of distribution in participants with moderate liver impairment resulted in a slightly longer mean t1/2 compared to participants with normal liver function. Geometric mean fu was similar across the three groups, with 8%, 7% and 9% in the normal liver function and mild or moderate impairment groups, respectively (Table 3). Point estimates for the total and unbound AUC and Cmax ratios compared to the control group were all within the no effect boundary of 0.80–1.25 (Fig. 1).

3.4 Pharmacodynamics3.4.1 Study 1: Age and Sex

Mean aPTT was similar at baseline (30–33 s) in all age and sex groups. Mean aPTT as ratio to baseline increased rapidly after administration of asundexian 25 mg in a concentration-dependent manner in all age and sex groups (Fig. S2a). Mean maximal ratio to baseline for aPTT was 1.55, 1.45, 1.52, 1.53, 1.47 and 1.50 in “young” male and females, “elderly” males and females, and “old” males and females, respectively, with corresponding median times to maximum aPTT in plasma (tmax) between 3.0 and 4.5 h. The exposure/response relationship for aPTT ratio to baseline was similar amongst all groups (Fig. 3a).

Fig. 3

Percentage ratio from baseline in aPTT versus plasma concentrations of asundexian in male and female participants in different age groups (study 1)a (a), in participants with CKD (study 2, Part A)b,c (b), in participants with ESKD (study 2, Part B)b,c (c) and in participants with liver impairment (study 3) (d)d. a The analysis in study 1 included all participants in the pharmacodynamics set. b The analysis in studies 2 and 3 included all participants in both the pharmacokinetics and pharmacodynamics set. c In study 2, values below the LLOQ were substituted by 1/2 LLOQ. d Outliers: aPTT values of one participant at 3 and 4 h post-dose administration were excluded from this figure as the purpose of the plots is to show the overall comparability between studies. The plot which includes the out liers is in Fig. S5. aPTT activated partial thromboplastin time, CKD chronic kidney disease, eGFR estimated glomerular filtration rate, ESKD end-stage kidney disease, LLOQ lower limit of quantification

Mean FXIa activity was similar at baseline (65–74%) in all groups. Mean FXIa activity as ratio to baseline decreased rapidly after administration of asundexian 25 mg in a concentration-dependent manner in all age and sex groups (Fig. S3a). Mean minimal ratio to baseline for FXIa activity was 0.09, 0.07, 0.07, 0.09, 0.10 and 0.05 in “young” males and females, “elderly” males and females and “old” males and females, respectively, with corresponding median times to minimum FXIa activity (tmin) between 2.5 and 4.0 h. The pharmacokinetic/pharmacodynamic relationship for FXIa activity ratio to baseline was similar between all groups (Fig. 4a).

Fig. 4

Percentage ratio from baseline in FXIa activity versus plasma concentrations of asundexian in male and female participants at different age groups (study 1) (a), in participants with kidney impairment (study 2, Part A) (b), in participants with ESKD (study 2, Part B) (c) and in participants with liver impairment (study 3) (d). The analysis sets consisted of participants in both the pharmacokinetics analysis set and the pharmacodynamics analysis set. Values below the LLOQ were substituted by 1/2 LLOQ. eGFR estimated glomerular filtration rate, ESKD end-stage kidney disease, FXIa activated factor XI, LLOQ lower limit of quantification

3.4.2 Study 2: Chronic Kidney Disease (eGFR G2, G3, G4)

Mean aPTT was similar at baseline (28–29 s) in all renal function groups. Mean aPTT as ratio to baseline increased rapidly after administration of asundexian 25 mg in a concentration-dependent manner in all renal function groups (Fig. S2b). Mean maximal ratio to baseline for aPTT was 1.49, 1.53, 1.59 and 1.57 in the matched-control and eGFR G2, G3 and G4 groups, respectively, with corresponding median tmax between 3.0 and 4.0 h. The pharmacokinetic/pharmacodynamic relationship for aPTT ratio to baseline was similar between all four groups (Fig. 3b).

Mean FXIa activity was similar at baseline (60–71%) in all renal function groups. Mean FXIa activity as ratio to baseline decreased rapidly after administration of asundexian 25 mg in a concentration-dependent manner in all renal function groups (Fig. S3b). Mean minimal ratio to baseline for FXIa activity was 0.08 in the eGFR G3 group, and not calculated for matched-control and eGFR G2 and G4 groups, as too many individual values were below the lower limit of quantification (LLOQ; 3.04%). The corresponding median tmin range across groups was 2.5–5.0 h.

The pharmacokinetic/pharmacodynamic relationship for FXIa activity ratio to baseline was similar between all four groups (Fig. 4b).

3.4.3 Study 2: End-Stage Kidney Disease on Dialysis

Mean aPTT was similar at baseline (29 s) in the ESKD group on days without and with dialysis and in the matched-control group. Mean aPTT as ratio to baseline increased rapidly after administration of asundexian 25 mg in a concentration-dependent manner in all groups (Fig. S2c). Mean maximal ratio to baseline for aPTT was 1.38, 1.41 and 1.54 in the ESKD group on days without and with dialysis and the matched-control group, respectively, with a corresponding median tmax range of 2.0–4.0 h. The pharmacokinetic/pharmacodynamic relationship for aPTT ratio to baseline was similar between all three groups (Fig. 3c).

Mean FXIa activity was similar at baseline, 82%, 80% and 69%, in the ESKD group on days without and with dialysis and in the matched-control group, respectively. Mean FXIa activity as ratio to baseline decreased rapidly after administration of asundexian 25 mg in a concentration-dependent manner in all groups (Fig. S3c). Mean minimal ratio to baseline for FXIa activity was 0.09 in the ESKD group on days without dialysis, 0.13 on days with dialysis and 0.08 for the matched-control group. The corresponding median tmin range was 2.0–4.5 h. The pharmacokinetic/pharmacodynamic relationship for FXIa activity ratio to baseline was similar between all three groups and was not affected by the dialysis procedure (Fig. 4c).

3.4.4 Study 3: Liver Impairment

Mean aPTT was similar at baseline (29, 30 and 33 s) in the matched-control (with normal liver function), mild and moderate liver impairment groups respectively. Mean aPTT as ratio to baseline increased rapidly after administration of asundexian 25 mg in a concentration-dependent manner in all three groups (Fig. S2d). Mean maximal ratio to baseline for aPTT was 1.43, 1.38 and 1.89 in the matched-control, mild and moderate liver impairment groups, respectively, with a corresponding median tmax between 3.0 and 4.0 h. The mean maximal aPTT (as ratio to baseline) was largely driven by a single outlier (results out of reference range at one timepoint); the same calculation without the outlier resulted in a mean maximal ratio to baseline of 1.55. The pharmacokinetic/pharmacodynamic relationship for aPTT ratio to baseline was similar between all three groups (Fig. 3d).

Mean FXIa activity at baseline negatively correlated with declining liver function: 62% in the matched-control group, 47% in the mild liver impairment group and 36% in the moderate liver impairment group. Mean FXIa activity as ratio to baseline decreased rapidly after administration of asundexian 25 mg in a concentration-dependent manner in all three groups (Fig. S3d). Mean minimal ratio to baseline for FXIa activity was 0.08, 0.08 and 0.07 in the matched-control, mild and moderate liver impairment groups, respectively, with a corresponding median tmax between 3.0 and 5.0 h. The pharmacokinetic/pharmacodynamic relationship for FXIa activity ratio to baseline was similar between all three groups (Fig. 4d).