Baseline demographics

A total of 212 healthy male participants were included in the four studies, comprising 118 White, 1 Black, and 93 Asian participants aged 18–50 years. In the European SRD study, the treated population included 48 healthy participants (BI 690517 2 mg dose group, n = 6; subsequent six dose groups, n = 7 each), as administration of the planned highest dose of 160 mg did not occur, and two participants allocated to the BI 690517 2 mg dose group discontinued the study prior to receiving study drug (i.e., during the run-in period from Day –1 until study drug administration) due to AEs, with only one participant subsequently replaced. Participant age ranged from 20 to 50 years and BMI from 19.1 to 29.6 kg/m2.

In the Chinese/Japanese SRD study, an extra dose group consisting of eight Chinese participants receiving BI 690517 60 mg was added due to a dosing error. Subsequently, an additional group of eight Chinese participants was recruited to replace the participants who erroneously received BI 690517 60 mg; consequently, the treated set included 56 male participants (Chinese, n = 32; Japanese, n = 24) who received BI 690517 or placebo, split into seven dose groups. Participant age ranged from 20 to 43 years and BMI from 18.6 to 24.9 kg/m2.

Of the 72 participants enrolled in the European MRD study who received BI 690517 or placebo (treated set; MRD part, n = 60; FE part, n = 12), 59 participants in the MRD part were White and 1 was Asian of Hispanic/Latino origin; all 12 participants in the FE part were White. One participant in the MRD part discontinued the study for personal reasons after the sixth intake of placebo; therefore, 71 participants completed the European MRD trial. In the treated set, participant age ranged from 20 to 50 years in the MRD part and from 22 to 50 years in the FE part; BMI ranged from 19.2 to 29.8 kg/m2 and from 19.7 to 29.3 kg/m2, respectively.

The Japanese MRD study enrolled 36 male Japanese participants aged 22 to 45 years, with BMI ranging from 18.9 to 24.2 kg/m2, all of whom received either BI 690517 or placebo. The baseline demographics for participants in all four studies are summarized in Table 1 and further details are provided in the Supplemental Information.

Table 1 Baseline demographics in the European and Chinese/Japanese SRD studies and the European and Japanese MRD studies (TS)Safety outcomes

Safety outcomes are described for the individual studies below. BI 690517 was well tolerated across the tested dose range, with no serious AEs, deaths, AEs leading to discontinuation of trial medication, or AEs of special interest in any of the four studies (Table 2, Supplemental Table S1, and Supplemental Table S2). Except for one instance of vessel puncture hematoma in the European SRD study (BI 690517 5 mg dose group), all treatment-emergent AEs (TEAEs) resolved by the end of the study periods. In all four studies, the frequency of drug-related AEs (primary outcome measure) did not show any dose-dependent trends. Apart from one instance of severe drug-related orthostatic hypotension in the European SRD trial (BI 690517 2 mg dose group), all drug-related AEs were of mild or moderate intensity.

Table 2 Summary of TEAEs in the European MRD study (TS)European SRD study

Drug-related AEs were reported by four participants (n/N = 4/48 [8.3%]): one participant in the BI 690517 2 mg dose group, two participants in the BI 690517 20 mg dose group (n = 3 events), and one participant in the BI 690517 80 mg dose group (Supplemental Table S1). The only system organ class for which more than one drug-related AE was reported was nervous system disorders (n/N = 3/48 [6.3%]): headache (n = 1; BI 690517 20 mg dose group), dysgeusia (n = 1; BI 690517 80 mg dose group), and involuntary muscle contractions (two events in one participant; BI 690517 20 mg dose group). TEAEs were reported by 27.1% of participants (n/N = 13/48).

Chinese/Japanese SRD study

Drug-related AEs were reported by 12 participants (n/N = 12/56 [21.4%]), five of whom received placebo and seven BI 690517 (3 mg, n = 1; 20 mg, n = 3; 80 mg, n = 3; Supplemental Table S2). The most frequent drug-related AEs by system organ class were nervous system disorders (headache [n = 2] or dizziness [n = 4]) and vascular disorders (orthostatic hypotension [n = 6]), which were each reported by 10.7% (n/N = 6/56) of participants. TEAEs were reported by 25.0% of participants (n/N = 14/56).

European MRD study

Drug-related AEs were reported by 10 participants (total, n/N = 10/72 [13.9%]: MRD part, n/N = 7/60 [11.7%]; FE part, n/N = 3/12 [25.0%]), all of whom received BI 690517 (3 mg, n = 2; 10 mg, n = 4; 20 mg, n = 1; 40 mg, n = 1; 80 mg, n = 2) (Table 2). In the FE part, drug-related AEs were reported by three participants in a fasted state and one participant following a standardized high-fat, high-calorie breakfast; all were in the BI 690517 10 mg dose group. Reported by 9.7% (n/N = 7/72) of participants, nervous system disorders were the most frequent drug-related AEs by system organ class in both study parts: in the MRD part (n/N = 4/60 [6.7%]), two participants experienced dizziness, one had a headache, and one reported with somnolence; and in the FE part (n/N = 3/12 [25.0%]), three participants had a headache following BI 690517 administration under fasted conditions. TEAEs were reported by 43.1% of participants (total, n/N = 31/72: MRD part, n/N = 28/60 [46.7%]; FE part, n/N = 3/12 [25.0%]).

Japanese MRD study

One participant in the BI 690517 40 mg dose group (n/N = 1/36 [2.8%]) reported a drug-related AE of increased alanine aminotransferase concentration. TEAEs were reported by 5.6% of participants (n/N = 2/36).

PK outcomes

Following BI 690517 intake, plasma exposure increased in a dose-dependent manner in all four SRD and MRD studies. The PK plasma profiles of BI 690517 were characterized by an early, sharp peak indicative of rapid absorption (Fig. 1, Supplemental Figs. S2 and S3). The median time to reach maximum plasma BI 690517 concentration ranged from 0.5 to 1.75 h (Table 3, Supplemental Tables S3 and S4). Dose-proportionality for exposure was observed across studies (Supplemental Table S5). Urinary excretion of BI 690517 increased with dose in all four studies; 24 h after dosing, ≤ 9.1% of the BI 690517 dose was excreted unchanged in urine (Supplemental Figs. S4–S7).

Fig. 1

Geometric mean plasma BI 690517 concentration over time after multiple oral administration of BI 690517 in the a) European MRD and b) Japanese MRD studies (PK set; semi-log scale). MRD multiple rising dose; PK pharmacokinetic

Table 3 Summary of BI 690517 PK parameters after single and multiple oral administration in the European MRD study (PK set)European studies

In the SRD study, following the initial peak, BI 690517 was rapidly cleared from the plasma with an apparent mean terminal plasma half-life (t½) of 4.51–6.30 h (Supplemental Table S3). On day 1 of the European MRD study, the apparent mean t½ was 4.45–5.57 h (Table 3). In the European MRD study, accumulation ratios based on the area under the plasma concentration–time curve of BI 690517 in plasma over the time interval from 0 h to τ (where τ = 24 h) (AUC0–τ) ranged from 1.04–1.12, suggesting no accumulation. Linearity index in the European MRD study was close to unity across the tested dose range (3–80 mg), indicating that the PK of BI 690517 are linear with respect to time (Supplemental Table S6).

A standardized high-fat meal did not affect the extent of BI 690517 10 mg absorption in the food effect part of the European MRD study; AUC0–∞ and AUC0–tz values were similar in a fasted state or following a standardized high-fat, high-calorie breakfast (Table 4). However, food consumption decreased the rate of absorption, delaying the time from last dose to Cmax by 1 h and reducing BI 690517 Cmax by approximately 23% (Table 3).

Table 4 Treatment-adjusted gMeans and relative bioavailability of BI 690517 administered in a fasted state or following a standardized high-fat, high-calorie breakfast in the food effect part of the European MRD study (PK set)Chinese/Japanese studies

There was no substantial difference in plasma exposure between Chinese and Japanese participants in the Chinese/Japanese SRD study (Supplemental Table S3). The apparent mean t½ was 4.43–6.13 h in the Chinese/Japanese SRD study and 5.40–6.00 h on day 1 of the Japanese MRD study (Supplemental Tables S3 and S4). In the Japanese MRD study, accumulation ratios based on AUC0–τ (where τ =24 h) ranged from 1.00–1.08, suggesting no accumulation. Linearity index measured in the Japanese MRD study was close to unity across the tested dose range (3–80 mg), indicating that the PK of BI 690517 are linear with respect to time (Supplemental Table S6).

PD outcomesPlasma aldosterone

The number of samples for which the aldosterone concentration was below the limit of quantification generally increased with dose in all four studies, consistent with a dose-dependent inhibition of aldosterone synthesis by BI 690517. In the MRD studies, higher doses of BI 690517 were associated with lower 12-h area under the effect curve (AUEC) of plasma aldosterone values at days 1 and 14, indicating that inhibition of aldosterone synthesis was maintained after multiple dosing for 14 days (Fig. 2). In the European MRD study, BI 690517 exposure > 10,000 nmol·h/L was not associated with further reductions in aldosterone AUEC. The levels of plasma aldosterone decreased markedly within 1–2 h of BI 690517 administration (Fig. 3, Supplemental Figs. S8–S10). In the Chinese/Japanese SRD study, strong inhibition was maintained in all dose groups 12 h post dose (Supplemental Fig. S11); however, 24 h post dose, the extent of aldosterone inhibition was greater in participants treated with BI 690517 ≥ 60 mg. Likewise, in the European SRD study, strong aldosterone inhibition was maintained 24 h post dose with BI 690517 ≥ 40 mg (Supplemental Fig. S12). In the MRD studies, a rebound effect on plasma aldosterone concentration following the last BI 690517 dose, which grew stronger until the last measurement, was observed for all active doses. In the European MRD study, this rebound effect was deemed to be dose dependent (Fig. 3).

Fig. 2

Comparison of mean AUEC0–12 (day 1) and mean AUEC0–12,ss (day 14) values for plasma aldosterone after multiple oral administration of BI 690517 or placebo in the a) European MRD and b) Japanese MRD studies (TS). AUEC area under the effect curve; MRD multiple rising dose; ss steady state; TS treated set

Fig. 3

Change in geometric mean plasma aldosterone concentration over time after multiple oral administration of BI 690517 in the European MRD study. Certain values were below the limit of quantification; therefore, the geometric mean could not be calculated for all time points. MRD multiple rising dose

Plasma corticosterone and 11-deoxycorticosterone

In the European and Chinese/Japanese SRD studies, plasma corticosterone concentrations followed the expected circadian rhythm, with no significant differences observed between dose groups (Supplemental Figs. S13 and S14). In the European SRD study, determination of 11-deoxycorticosterone concentrations was attempted, but this analyte could not be differentiated from 17-hydroxyprogesterone; therefore, results were not interpretable. In the Chinese/Japanese SRD study, one-third of the 11-deoxycorticosterone data points were below the lower limit of quantification. However, in the MRD studies, levels of aldosterone precursors increased on days 14 and 15, relative to the values at day 1, in the highest BI 690517 dose groups: in the European MRD study, plasma corticosterone levels were elevated in the 80 mg dose group and 11-deoxycorticosterone levels were increased in the 40 and 80 mg dose groups; in comparison, in the Japanese MRD study, plasma corticosterone and 11-deoxycorticosterone levels were increased in the 40 and 80 mg dose groups (Fig. 4 and Supplemental Fig. S15).

Fig. 4

Change in geometric mean plasma a) corticosterone, b) 11-deoxycorticosterone, c) cortisol, and d) 11-deoxycortisol concentration over time after multiple oral administration of BI 690517 or placebo in the European MRD study. MRD multiple rising dose

Plasma cortisol and 11-deoxycortisol

In all four studies, there was no clear dose-dependent effect of BI 690517 on plasma cortisol (Fig. 4 and Supplemental Figs. S13–S15), which followed the expected circadian rhythm: plasma cortisol reached its peak concentration in the morning and lowest concentration in the evening. In the Chinese/Japanese SRD study, despite similar baseline levels, one Japanese participant in the 80 mg dose group had a plasma 11-deoxycortisol concentration 3- to 25-fold higher than other participants in the 80 mg dose group from 1–4 h post dose. Consistently, in the European MRD and Japanese MRD studies, there was a marked increase in plasma 11-deoxycortisol on days 14 and 15 in the 40 mg dose group (in the Japanese MRD study) and in the 80 mg dose groups (in both studies) compared with baseline, suggesting that the two highest doses of BI 690517 may increase plasma 11-deoxycortisol concentration.

Plasma renin

The SRD studies did not show any clear dose-dependent effect of BI 690517 on plasma renin (Supplemental Fig. S16). However, in the European MRD study, despite plasma renin concentrations being similar across all dose groups on day 1, on day 14, plasma renin concentrations tended to be higher in groups exposed to higher doses of BI 690517 (Supplemental Fig. S17). This dose-dependent increase remained apparent 48 h after administration of the last BI 690517 dose.

Plasma ACTH

In the two SRD studies and the European MRD study, plasma ACTH concentration over time was similar across all dose groups, suggesting no effect of BI 690517 on plasma ACTH (Supplemental Figs. S18 and S19). However, in the European MRD study, the increase in plasma cortisol following ACTH challenge was less pronounced in participants receiving higher BI 690517 doses. Plasma ACTH followed the expected circadian rhythm, reaching a peak in the morning and its lowest concentration in the evening.

Urine aldosterone and cortisol

In all four studies, most measurements for urine aldosterone were below the lower limit of quantification and thus were not interpretable. Single doses of BI 690517 did not affect urinary cortisol excretion. In the European MRD study, following 14 days of treatment with BI 690517, urinary cortisol excretion was reduced in all BI 690517 dose groups, except for the 10 mg dose group, in which a slight increase was seen compared with day 1 (Supplemental Table S7). In the Japanese MRD study, following 14 days of treatment, urinary cortisol excretion was slightly increased in participants receiving placebo or BI 690517 3 mg, and slightly reduced in participants receiving BI 690517 ≥ 40 mg, compared with day 1 (Supplemental Table S7). The changes in urinary cortisol excretion reported in both MRD studies were not dose dependent.

Plasma and urine sodium and potassium

No dose-dependent changes in serum potassium concentration over time (Supplemental Figs. S20–S22) or dose-dependent trends in urinary sodium and potassium excretion were observed in any of the four studies. The mean change from baseline in serum potassium was generally within 5–6% and did not exceed 11% in any of the four studies. None of the participants in the Chinese/Japanese SRD and the Japanese MRD study had elevated serum potassium levels (≥ 5.0 mmol/L). Elevated serum potassium was reported at least once during the treatment period by 8.3% of participants in the European SRD study (n/N = 4/48: n = 1 each in the BI 690517 0.7, 5, 10, and 20 mg dose groups) and 28.9% of participants treated with BI 690517 in the European MRD study (n/N = 13/45: n = 4, BI 690517 20 mg; n = 3, BI 690517 40 mg; and n = 2 each in BI 690517 3, 10, and 80 mg dose groups). None of the participants who received placebo in the European MRD study had serum potassium levels ≥ 5.0 mmol/L during the treatment period.

The mean sodium/potassium urinary excretion ratio increased from day − 1 to day 1 in all treatment groups in the two SRD studies, except for the BI 690517 2 mg dose group in the European SRD study; in this study, single doses of BI 690517 ≥ 40 mg increased mean 24-h urinary sodium excretion compared with day − 1 (Supplemental Table S8). Likewise, in the Chinese/Japanese SRD study, higher doses of BI 690517 (20 and 80 mg) increased mean 24-h urinary sodium excretion compared with placebo (Supplemental Table S9). In the European SRD study, a clear reduction in urinary potassium excretion was seen from day − 1 to day 1 with all tested doses of BI 690517, and in the Chinese/Japanese SRD study, urinary potassium excretion was reduced in all treatment groups compared with placebo (Supplemental Tables S10 and S11).

No dose-dependent changes in urinary sodium and potassium excretion over 24 h of treatment were observed following 14 days of multiple dosing in the two MRD studies (Supplemental Tables S12 and S13). In the European MRD study, the change in sodium/potassium urinary excretion ratio from day 1 to day 14 ranged from − 0.11 to + 1.48. Mean urinary sodium excretion was lower in all study arms (BI 690517 and placebo) except for the BI 690517 40 mg dose group on day 14 compared with day 1 (Supplemental Table S12). In comparison, urinary potassium excretion was reduced in placebo recipients and participants treated with BI 690517 3 or 20 mg, and increased in participants treated with BI 690517 10, 40, or 80 mg on day 14 compared with day 1 (Supplemental Table S13). In the Japanese MRD study, changes in urinary sodium excretion were small and not dose dependent (Supplemental Table S12). Additionally, no clear difference in 24-h urinary potassium excretion was seen in any of the dose groups, except the BI 690517 80 mg dose group, for which a small increase was seen (Supplemental Table S13).