Novel Aldosterone Synthase Inhibitor Cuts Albuminuria in Phase II Trial

PHILADELPHIA — An oral investigational aldosterone synthase inhibitor (ASI) cut albuminuria by nearly 40% in people in chronic kidney disease (CKD) in a phase II trial.

The 10-mg dose of ASI BI 690517 yielded an average 37.4% (95% CI -52.2 to -18.2%) greater reduction in urine albumin-creatinine ratio (UACR) from baseline to week 14 compared with placebo — the greatest reduction of three doses tested — Katherine Tuttle, MD, of University of Washington in Spokane, reported at the American Society of Nephrology’s Kidney Week.

The 20-mg dose — which was the highest dose tested — also yielded significantly greater UACR reductions compared with placebo (-34.9%, 95% CI -50.7 to -14.0%). The 3-mg dose numerically reduced average UACR from baseline, but the difference was not significant (-20.3%, 95% CI -38.6 to 3.4%).

Tuttle’s group also tested all three doses of BI 690517 on a background of the SGLT2 inhibitor empagliflozin (Jardiance). Following a similar pattern, the 10-mg dose yielded the greater UACR reductions compared with placebo:

• 20 mg + empagliflozin: -33.2% (95% CI -46.5 to -16.8%)
• 10 mg + empagliflozin: -39.5% (95% CI -51.8 to -24.0%)
• 3 mg + empagliflozin: -9.4% (95% CI -27.1 to 12.7%)

“Aldosterone synthase inhibition is a promising new therapy that may add benefit to SGLT2 inhibition for CKD with or without type 2 diabetes,” Tuttle said during her presentation.

More patients who took the combination of BI 690517 plus empagliflozin were able to achieve a 30% or greater UACR reduction from baseline, achieving one of the trial’s secondary endpoints (ranging from 70% with the 10-mg dose to 33% with the 3-mg dose vs 22% with placebo). Without empagliflozin, this ranged from 51% to 29% versus 15% with placebo.

BI 690517 alone didn’t significantly impact systolic blood pressure throughout the 14-week treatment period compared with placebo. However, with a background of empagliflozin, reductions were significant: -8.25 mmHg for 20 mg, -7.81 mmHg for 10 mg, and -7.02 mmHg for 3 mg, compared with placebo.

There were no significant changes in morning serum cortisol on any dosage with or without empagliflozin, but all doses achieved a significant drop in placebo-corrected plasma aldosterone levels, both without empagliflozin (-62% for 20 mg, -49% for 10 mg, and -41% for 3 mg) and with empagliflozin (-66% for 20 mg, -56% for 10 mg, and -39% for 3 mg).

Average serum potassium increased between 0.25 to 0.33 mmol/L across the BI 690517-only doses, though this was slightly mitigated by adding empagliflozin. With the combination, only the two higher doses had significant increases in serum potassium (0.24 mmol/L with 20 mg and 0.32 mmol/L with 10 mg).

As for eGFR throughout the trial, all groups had either a numerically or statistically significant drop. Compared with placebo, there were significant eGFR changes seen for the following groups taking BI 690517:

• 20 mg: -2.96 mL/min/1.73 m² (95% CI -5.80 to -0.11)
• 10 mg: -3.59 mL/min/1.73 m² (95% CI -6.68 to -0.50)
• 20 mg + empagliflozin: -3.71 mL/min/1.73 m² (95% CI -7.21 to -0.21)

The investigational treatment was generally safe and well-tolerated, with a similar rate of any adverse events across all study arms. Investigator-reported hyperkalemia occurred more frequently among those taking BI 690517, with patients taking the 20-mg dose without empagliflozin having the most reports (24%) followed by those taking the 10-mg dose plus empagliflozin (21%).

Among those taking BI 690517, 4% discontinued treatment due to hyperkalemia versus 0% taking placebo. There were no fatal hyperkalemia events. Six participants on the study drug had a serum potassium over 6 mEq/L versus only 1 on placebo. Most cases of hyperkalemia didn’t end up requiring treatment (86%).

Other adverse events included hypotension, acute kidney injury, and adrenal insufficiency.

A total of 714 adults with CKD with or without type 2 diabetes were recruited for this phase II trial. All were receiving stable background treatment with an ACEi or ARB for at least 4 weeks prior to screening. There were between 71 and 76 participants in each of the eight study arms. The average age was around 64, about 60% were white, 30% Asian, and the majority in each study arm had diabetes. Mean baseline eGFR ranged from 49.6 to 56.1 mL/min/1.73 m² and median UACR ranged from 348 to 464 mg/G.

“This therapeutic strategy will be tested further in a large phase III clinical trial,” Tuttle added, announcing the EASi-KIDNEY trial. “The trial will begin recruitment next year and the aim is to test the efficacy and safety of the aldosterone synthase inhibitor BI 690517 versus matching placebo, given on top of a standard of care including empagliflozin 10 mg daily. The study will recruit and follow about 11,000 patients with chronic kidney disease.”

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