Efficacy and safety of aldosterone synthase inhibition with and without empagliflozin for chronic kidney disease: a randomised, controlled, phase 2 trial.

Background: Excess aldosterone accelerates chronic kidney disease progression. This phase 2 clinical trial assessed BI 690517, an aldosterone synthase inhibitor, for efficacy, safety, and dose selection.
Methods: This was a multinational, randomised, controlled, phase 2 trial. People aged 18 years or older with an estimated glomerular filtration rate (eGFR) of 30 to less than 90 mL/min/1·73 m ² , a urine albumin to creatinine ratio (UACR) of 200 to less than 5000 mg/g, and serum potassium of 4·8 mmol/L or less, taking an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, were enrolled. Participants were randomly assigned (1:1) to 8 weeks of empagliflozin or placebo run-in, followed by a second randomisation (1:1:1:1) to 14 weeks of treatment with once per day BI 690517 at doses of 3 mg, 10 mg, or 20 mg, or placebo. Study participants, research coordinators, investigators, and the data coordinating centre were masked to treatment assignment. The primary endpoint was the change in UACR measured in first morning void urine from baseline (second randomisation) to the end of treatment. This study is registered with ClinicalTrials.gov (NCT05182840) and is completed.
Findings: Between Feb 18 and Dec 30, 2022, of the 714 run-in participants, 586 were randomly assigned to receive BI 690517 or placebo. At baseline, 33% (n=196) were women, 67% (n=390) were men, 42% (n=244) had a racial identity other than White, and mean participant age was 63·8 years (SD 11·3). Mean baseline eGFR was 51·9 mL/min/1·73 m ² (17·7) and median UACR was 426 mg/g (IQR 205 to 889). Percentage change in first morning void UACR from baseline to the end of treatment at week 14 was -3% (95% CI -19 to 17) with placebo, -22% (-36 to -7) with BI 690517 3 mg, -39% (-50 to -26) with BI 690517 10 mg, and -37% (-49 to -22) with BI 690517 20 mg monotherapy. BI 690517 produced similar UACR reductions when added to empagliflozin. Investigator-reported hyperkalaemia occurred in 10% (14/146) of those in the BI 690517 3 mg group, 15% (22/144) in the BI 690517 10 mg group, and 18% (26/146) in the BI 690517 20 mg group, and in 6% (nine of 147) of those receiving placebo, with or without empagliflozin. Most participants with hyperkalaemia did not require intervention (86% [72/84]). Adrenal insufficiency was an adverse event of special interest reported in seven of 436 study participants (2%) receiving BI 690517 and one of 147 participants (1%) receiving matched placebo. No treatment-related deaths occurred during the study.
Interpretation: BI 690517 dose-dependently reduced albuminuria with concurrent renin-angiotensin system inhibition and empagliflozin, suggesting an additive efficacy for chronic kidney disease treatment without unexpected safety signals.
Funding: Boehringer Ingelheim.
Competing Interests: Declaration of interests KRT reports grants for investigator-initiated research from NIDDK, NHLBI, NCATS, NIMHD, NIH Data Science office, Travere, Bayer, and Goldfinch Bio; contracts from CDC; consulting fees from Boehringer Ingelheim, Janssen, Novo Nordisk, AstraZeneca, Bayer, Eli Lilly, Gilead, and Merck Sharp & Dohme; payment for manuscript writing for Boehringer Ingelheim, Novo Nordisk, Bayer, Eli Lilly, and Gilead; payment of honoraria for Novo Nordisk, AstraZeneca, Bayer, Eli Lilly, and Gilead; payment for travel for Novo Nordisk; travel to meetings from Novo Nordisk; chair and member of a data safety monitoring committee for NIDDK and George Clinical; and leadership role for the American Society of Nephrology. MEC reports grants for investigator-initiated research and research funding from Baxter and Fresenius; and payment of honoraria for lectures, presentations, and education events from AstraZeneca, Fresenius, Bayer, Pfizer, and Bracepharma. MLC reports research grant support from NIH and NIDDK (all to the University of Minnesota and Cleveland Clinic) and research grant support sponsored by Bayer Pharmaceuticals (all to the University of Minnesota); consulting fees from Bayer Pharmaceuticals, Novo Nordisk, and AstraZeneca; payment for speaker bureaus and educational events from Bayer Pharmaceuticals; payment of honoraria for lectures and educational events from Cardiorenal Connections, Heart in Diabetes, Translational Medicine Academy, and the American College of Cardiology; support to attend investigator meetings for Kidney Precision Medicine Project from the NIH and NIDDK, American Diabetes Association meetings from NIH and NIDDK, and University of Minnesota and American Society of Nephrology meetings from NIH and NIDDK and Cleveland Clinic Foundation (all to the University of Minnesota); participation on and site principle investigator for the Data Safety Monitoring Board for Preventing Early Renal Loss in Diabetes Study for NIH and NIDDK (all to the University of Minnesota); and attendee of Kidney Disease Improving Global Outcomes writing group meetings. DC reports research grants from Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca, CSL Behring, and Novo Nordisk; consulting fees from Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi Tanabe, AbbVie, Janssen, Bayer, Prometic, Bristol Myers Squibb, Maze, Gilead, CSL Behring, Otsuka, Novartis, Youngene, Lexicon, Inversago, GSK, and Novo Nordisk; payment of honoraria for lectures and advisory boards from Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi Tanabe, Janssen, Bayer, and Novo Nordisk; support for traveling to and attending meetings from Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Janssen, Bayer, and Novo Nordisk; and receipt of a drug for research from AstraZeneca. HJLH reports funding to conduct clinical trials from AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, and Novo Nordisk (all to the University of Groningen); consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Chinook, CSL Behring, DImerix, Eli Lilly, Fresenius, Gilead, Janssen, Novo Nordisk, Novartis, and Travere Therapeutics; payment of honoraria for lectures from AstraZeneca, Novo Nordisk, and Bayer; support for traveling to and attending the American Diabetes Association meeting and American Society of Nephrology meeting from AstraZeneca and Eli Lilly (to HJLH and the University of Groningen); and receipt of the study drug from AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, and Novo Nordisk. MN reports donations for research through Shogaku Kifu practice from KyowaKiirin, Mitsubishi Tanabe, Chugai, Boehringer Ingelheim, Torii, Takeda, Daiichi Sankyo, and JT; consulting fees from KyowaKiirin and Mitsubishi Tanabe; and payment of honoraria for lectures from KyowaKiirin, Mitsubishi Tanabe, Bayer, Astellas, JT, and AstraZeneca. RCR reports participation as a trial investigator for Novo Nordisk and AstraZeneca; consulting fees from Boehringer Ingelheim, Bayer, AstraZeneca, Chinook, and Novo Nordisk; payment of honoraria for lectures from AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Amgen, and Bayer; and voluntary membership of the steering committee for World Kidney Day and of the Diabetes Committee. AS reports research contracts from Boehringer Ingelheim, Mineralysis, ProKidney, Reata, and Novartis; consulting fees from Boehringer Ingelheim, Ardelyx, and Pro Kidney; payment of honoraria for presentations from ProKidney, Boehringer Ingelheim, AstraZeneca, and Bayer; and participation on an Advisory Board for Travere, Boehringer Ingelheim, and Reata. DdZ reports consulting fees from Bayer, Fresenius, and Travere. PR reports grants and payment of honoraria for lectures, educational events, and steering group participation from AstraZeneca, Bayer, and Novo Nordisk (all to the Steno Diabetes Center Copenhagen); payment of honoraria for lectures and participation in advisory boards from Boehringer Ingelheim, Sanofi, Abbott, and Astellas (all to the Steno Diabetes Center Copenhagen). SJH, LC, SVS, and ZS are employees of Boehringer Ingelheim. All other authors declare no competing interests.
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