In a phase 2 trial, 14-week treatment with BI 690517, in addition to RAASi therapy, dose-dependently reduced albuminuria compared with placebo in CKD patients, either as monotherapy or in combination with empagliflozin. The drug’s safety profile was deemed acceptable.

This summary is based on the publication of Tuttle KR, Hauske SJ, Canziani ME, et al. - Efficacy and safety of aldosterone synthase inhibition with and without empagliflozin for chronic kidney disease: a randomised, controlled, phase 2 trial. Lancet. 2024 Jan 27;403(10424):379-390. doi: 10.1016/S0140-6736(23)02408-X

Introduction and methods

Background

ACE inhibitors, ARBs, and nonsteroidal MRAs do not completely block the effects of aldosterone and also increase the risk of hyperkalemia [1-8]. As aldosterone synthase inhibitors directly lower aldosterone production, they possess the potency of enhancing therapeutic effectiveness in patients with CKD [6,7,9-11].

Aim of the study

The study aim was to assess the efficacy and safety of multiple oral doses of BI 690517—a potent, highly selective aldosterone synthase inhibitor—alone or in combination with an SGLT2 inhibitor in CKD patients who were on stable background RAASi therapy.

Methods

This was a multinational, placebo-controlled, double-blind, phase 2 RCT in which 586 patients with CKD (eGFR 30–89 mL/min/1.73 m², urine albumin-to-creatinine ratio (UACR) 200–4999 mg/g, and serum potassium ≤4.8 mmol/L), with or with no T2D, who were taking the maximum tolerated dose of an ACE inhibitor or ARB were enrolled. Participants were randomized (in a 1:1 ratio) to empagliflozin 10 mg once daily or placebo for a run-in period of 8 weeks, followed by a second randomization (1:1:1:1 ratio) to oral BI 690517 (3, 10, or 20 mg) once daily or placebo for 14 weeks. A main exclusion criterion was a clinical indication for MRA treatment.

Outcomes

The primary endpoint was the change in UACR measured in first-morning void urine from baseline (of the second randomization) to 14 weeks. Secondary endpoints included the proportion of participants with an absolute decrease in first-morning void UACR of ≥30% and ≥15% from baseline to 14 weeks. Additional endpoints were, among others, changes in serum potassium, eGFR, and markers of target engagement (plasma aldosterone) and selectivity (serum cortisol) from baseline to 14 weeks. Safety endpoints included adverse events, serious adverse events, adverse events of special interest (such as ketoacidosis and adrenal insufficiency), cortisol response, and investigator-reported hyperkalemia.

Main results

Efficacy

• At 14 weeks, the percentage change in first-morning void UACR from baseline was –3% (95%CI: –19% to 17%) in patients treated with placebo, –22% (95%CI: –36% to –7%) with BI 690517 3 mg, –39% (95%CI: –50% to –26%) with BI 690517 10 mg, and –37% (95%CI: –49% to –22%) with BI 690517 20 mg.
• In patients receiving both BI 690517 and empagliflozin, the percentage change in first-morning void UACR was –11% (95%CI: –23% to 4%), –19% (95%CI: –31% to –5%), –46% (95%CI: –54% to –36%), and –40% (95%CI: –49% to –30%), respectively.
• In the BI 690517 10-mg dose group, a ≥30% UACR reduction from baseline was observed in 51% of the patients on monotherapy (OR for 10 mg vs. placebo: 6.09; 95%CI: 2.64–14.08) and 70% of those also receiving empagliflozin (OR for 10 mg vs. placebo: 8.42; 95%CI: 3.73–19.02).
• Across the BI 690517 doses, the largest response rate for a ≥15% UACR reduction from baseline was seen in patients taking both BI 690517 10 mg and empagliflozin (OR for 10 mg vs. placebo: 6.08; 95%CI: 2.73–13.57).

Additional endpoints

• The placebo-corrected mean change in serum potassium from baseline to 14 weeks was 0.25 mmol/L (95%CI: 0.08–0.41) with BI 690517 3 mg, 0.33 mmol/L (95%CI: 0.15–0.51) with BI 690517 10 mg, and 0.32 mmol/L (95%CI: 0.15–0.49) with BI 690517 20 mg. In all BI 690517 dose groups, placebo-corrected mean serum potassium changes were similar or smaller with BI 690517 and empagliflozin combination therapy.
• From baseline to 14 weeks, small decreases in eGFR were observed in response to BI 690517 with or with no concurrent empagliflozin (placebo-corrected mean changes ranged from –0.95 to –3.71 mL/min/1.73 m²).
• BI 690517 treatment resulted in a dose-dependent reduction of the plasma aldosterone exposure (area under the curve). The placebo-corrected reduction after 14 weeks was 62% (95%CI: 41%–76%) with BI 690517 20 mg monotherapy and 66% (95%CI: 53%–75%) with BI 690517 and empagliflozin combination therapy.
• Compared with placebo, there were no mean decreases in morning serum cortisol concentrations from baseline to 14 weeks in any of the BI 690517 monotherapy or BI 690517 and empagliflozin combination groups.

Safety

• For the safety assessments, the monotherapy and combination therapy groups were pooled. The frequency of any adverse event was similar among the treatment groups (54% for placebo, 55% for BI 690517 3 mg, 61% for BI 690517 10 mg, and 62% for BI 690517 20 mg). The frequencies of any serious adverse event were 7%, 5%, 8%, and 8%, respectively.
• There were no cases of severe drug-induced liver injury or ketoacidosis and no treatment-related deaths.
• Adrenal insufficiency was observed in 7 of 436 patients (2%) treated with any BI 690517 dose and 1 of 147 (1%) of the placebo-treated patients.
• Hyperkalemia occurred in 6% of the patients receiving placebo, 10% of those on BI 690517 3 mg, 15% of those taking BI 690517 10 mg, and 18% in the BI 690517 20-mg group, with or with no empagliflozin. There were no fatal hyperkalemia events, and most patients with hyperkalemia (86%) did not require intervention.

Conclusion

This phase 2 RCT among CKD patients showed that 14-week treatment with the aldesterone synthase inhibitor BI 690517, in addition to stable RAASi therapy, dose-dependently reduced albuminuria (up to ~42% for the 10-mg dose) compared with placebo, either as monotherapy or in combination with empagliflozin. BI 690517 treatment was associated with higher rates of hyperkalemia compared with placebo, but most cases did not require medical intervention or drug discontinuation. The safety profile of BI 690517, with or with no empagliflozin, was deemed acceptable by the authors. They conclude that “[u]sing BI 690517 along with empagliflozin might offer the potential for additive kidney protection, while mitigating hyperkalemia risk.”

Find this article online at Lancet.

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