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Purpose <p>In chronic kidney disease (CKD), raised plasma aldosterone levels are strongly associated with adverse cardiorenal outcomes. Current standard of care may improve outcomes; however, elevated aldosterone levels often persist. We report safety results for BI&#xa0;690517 (vicadrostat), a potent, selective aldosterone synthase inhibitor under investigation for CKD.</p> Methods <p>Four phase 1 studies of BI&#xa0;690517 conducted in healthy European/Chinese/Japanese men: two single rising dose (SRD) and two multiple rising dose (MRD) studies. Primary endpoint: proportion of participants with investigator-defined drug-related adverse events (AEs).</p> Results <p>Single and multiple doses of BI&#xa0;690517 ≤ 80&#xa0;mg (0.7–80&#xa0;mg [European SRD]; 3–80&#xa0;mg [Chinese/Japanese SRD and MRD]) were well tolerated. Proportions of participants with drug-related AEs: European SRD, 8.3% (4/48); Chinese/Japanese SRD, 21.4% (12/56); European MRD, 13.9% (10/72); Japanese MRD, 2.8% (1/36). No serious AEs, deaths, or AEs leading to treatment discontinuation were reported; one AE of severe orthostatic hypotension occurred (European SRD). Plasma exposure to BI&#xa0;690517 increased dose dependently; median time to maximum concentration was 0.50–1.75&#xa0;h and mean half-life was 4.4–6.3&#xa0;h. Exposure was slightly higher in Asians versus Europeans and may relate to lower body weight in Asian participants. A standardized high-fat/high-calorie meal reduced the rate, but not extent, of BI&#xa0;690517 absorption. Plasma aldosterone concentrations decreased markedly 1–2&#xa0;h after BI&#xa0;690517 administration; decreases were more pronounced with increasing BI&#xa0;690517 doses.</p> Conclusion <p>BI&#xa0;690517 was well tolerated and demonstrated dose-dependent inhibition of aldosterone synthesis. Larger studies are warranted to confirm these findings.</p>

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Phase 1 studies of the safety, tolerability, pharmacokinetics, and pharmacodynamics of BI 690517 (vicadrostat), a novel aldosterone synthase inhibitor, in healthy male volunteers

  • 期刊论文

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  • 发表日期：

    2025年2月3日

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  • Friedrich Schulze,
  • Jennifer Schaible,
  • Markus Goettel,
  • Yuko Tanaka,
  • Kathrin Hohl,
  • Armin Schultz,
  • In-Jin Jang

摘要

Purpose

In chronic kidney disease (CKD), raised plasma aldosterone levels are strongly associated with adverse cardiorenal outcomes. Current standard of care may improve outcomes; however, elevated aldosterone levels often persist. We report safety results for BI 690517 (vicadrostat), a potent, selective aldosterone synthase inhibitor under investigation for CKD.

Methods

Four phase 1 studies of BI 690517 conducted in healthy European/Chinese/Japanese men: two single rising dose (SRD) and two multiple rising dose (MRD) studies. Primary endpoint: proportion of participants with investigator-defined drug-related adverse events (AEs).

Results

Single and multiple doses of BI 690517 ≤ 80 mg (0.7–80 mg [European SRD]; 3–80 mg [Chinese/Japanese SRD and MRD]) were well tolerated. Proportions of participants with drug-related AEs: European SRD, 8.3% (4/48); Chinese/Japanese SRD, 21.4% (12/56); European MRD, 13.9% (10/72); Japanese MRD, 2.8% (1/36). No serious AEs, deaths, or AEs leading to treatment discontinuation were reported; one AE of severe orthostatic hypotension occurred (European SRD). Plasma exposure to BI 690517 increased dose dependently; median time to maximum concentration was 0.50–1.75 h and mean half-life was 4.4–6.3 h. Exposure was slightly higher in Asians versus Europeans and may relate to lower body weight in Asian participants. A standardized high-fat/high-calorie meal reduced the rate, but not extent, of BI 690517 absorption. Plasma aldosterone concentrations decreased markedly 1–2 h after BI 690517 administration; decreases were more pronounced with increasing BI 690517 doses.

Conclusion

BI 690517 was well tolerated and demonstrated dose-dependent inhibition of aldosterone synthesis. Larger studies are warranted to confirm these findings.