Lorundrostat, a novel aldosterone synthase inhibitor (ASI), added to SGLT2 inhibitors significantly reduced automated office systolic blood pressure (AOSBP) and albuminuria in patients with chronic kidney disease (CKD) and uncontrolled hypertension, the results of a new phase 2 clinical trial showed. 

“This provides a new opportunity to facilitate blood pressure control in people with CKD,” said study investigator Matthew Weir, MD, professor and chief of the Division of Nephrology at the University of Maryland School of Medicine in Baltimore.

The findings, which were presented at Kidney Week 2025: American Society of Nephrology Annual Meeting, provide the first report of the safety and efficacy of this agent in patients with CKD and uncontrolled hypertension.

Approximately 37 million individuals in the US have CKD and 60%-90% have concurrent hypertension, Weir told meeting attendees. Furthermore, he said 76% of individuals with CKD and hypertension have uncontrolled blood pressure despite treatment with multiple anti-hypertensive medications. 

Lorundrostat, a selective aldosterone synthetase, inhibits CYP11B2, which is the enzyme responsible for raising aldosterone levels. It has demonstrated efficacy and safety in previous phase 2 and phase 3 studies of patients with uncontrolled hypertension, including treatment resistant hypertension, said Weir.

Explore-CKD

The Explore-CKD trial (NCT06150924) was a randomized, double-blind, placebo-controlled, crossover study. It included 59 adults with uncontrolled hypertension and CKD, with baseline estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73m² and urinary albumin-creatinine ratio (UACR) 200-5000 mg/g, who were on stable doses of SGLT2i and ACEi/ARB. 

The individuals were randomized to lorundrostat 25 mg/day followed by placebo (LP group, n = 30) or placebo followed by lorundrostat 25 mg/day (PL group, n = 29) in 4-week treatment sequences with a 4-week washout in between. The primary endpoint was the change from baseline in AOSBP and placebo-adjusted change from baseline in spot UACR and cystatin-C eGFR. 

The mean age of study participants was 64.6 years, and the mean BMI was 33. The cohort was 69.5% male and 76.3% had diabetes. The mean ± SD baseline values were AOSBP 149 ± 10.4 mm Hg and eGFR 43 ± 15.0 mL/min/1.73m². Weir, who presented the findings at the meeting, said the geometric mean baseline spot UACR was 516 ± 2.5 mg/g. 

The least square mean reduction in AOSBP was 9.3 mm Hg (90% CI, -12.5 to -6.1; P < .0001) for lorundrostat and 1.8 mm Hg (90% CI, -5.0 to 1.5, ns) for placebo (placebo-adjusted reduction of 7.5 mm Hg; 90% CI, -11.6 to -3.4; P = .0024). 

The placebo-adjusted reduction in geometric mean of spot UACR was 25.6% (90% CI, -35.8 to -13.7; P = .0015). The placebo-adjusted change in eGFR was -4.6% (90% CI, -8.1 to -1.0; P = .036). 

“We were not surprised by any of the findings,” Weir told Medscape Medical News. 

In addition, lorundrostat “was well tolerated with minor changes in serum potassium,” he reported. A total of three participants discontinued treatment due to four adverse events: hyperkalemia, acute kidney injury, retinal detachment, and CKD.

Complementary Benefits With SGLT2 Inhibition

Nephrologist George Thomas, MD, assistant professor at the Cleveland Clinic in Ohio, who was not involved in the study, said the observed placebo-adjusted reduction of 7.5 mm Hg in AOSBP and 25.6% decline in UACR would suggest complementary benefits along with SGLT2 inhibition. 

“Hyperkalemia was reported as modest and manageable. However, its implications warrant further evaluation in real-world settings particularly in those with lower GFR,” he cautioned. 

“Overall, this trial underscores the therapeutic potential of dual therapy in CKD, a strategy that could improve [blood pressure] control and kidney protection in a population where hypertension remains difficult to manage,” Thomas told Medscape Medical News.

Weir reports consulting fees from Mineralys Therapeutics, AstraZeneca, Bayer, Corcept, Novo Nordisk, Vera, and CSL Vifor. Thomas had no disclosures to report.