Lorundrostat reduces blood pressure and urine albumin-to-creatinine ratio in patients with chronic kidney disease (CKD) and hypertension.
Positive data from the phase 2 Explore-CKD clinical trial (NCT06150924)1 show that lorundrostat (Mineralys Therapeutics) demonstrated clinically meaningful reductions in both systolic automated office blood pressure (AOBP) and urine albumin-to-creatinine ratio (UACR) in patients with both chronic kidney disease (CKD) with albuminuria and hypertension. The investigators noted that lorundrostat met the trial’s primary end point while showing a favorable safety and tolerability profile.1,2
Trial Name: Efficacy and Safety of Lorundrostat in Addition to Sodium-Glucose Cotransporter-2 Inhibitors (SGLT2i) in Subjects with Hypertension and Chronic Kidney Disease (CKD) with Albuminuria
ClinicalTrials.gov ID: NCT06150924
Sponsor: Mineralys Therapeutics Inc.
Completion Date (Estimated): May 2025
Lorundrostat is an oral, highly selective aldosterone synthase inhibitor (ASI) under development for the treatment of uncontrolled hypertension (uHTN) or resistant hypertension (rHTN), as well as CKD and obstructive sleep apnea. Lorundrostat was designed to reduce aldosterone levels by inhibiting CYP11B2, which is the enzyme responsible for its production. Additionally, it has 374-fold selectivity for aldosterone-synthase inhibition compared with cortisol-synthase inhibition in vitro, as well as an observed half-life of about 10 to 12 hours. Lorundrostat demonstrated an approximate 40% to 70% reduction in plasma aldosterone concentration in patients with hypertension.2
CKD is characterized by the gradual loss of kidney function and is estimated by the CDC to affect over 10% of the global population. Nationwide, CKD is considered one of the leading causes of mortality. An estimated 1 in 7 (approximately 37 million) US adults have CKD, and approximately 22 million people in the US are living with both hypertension and CKD. Because these conditions are linked—sustained hypertension may contribute to impaired kidney function, and progressive decrease in kidney function may lead to worsening blood pressure control—the risk of cardiovascular disease and mortality rises significantly when CKD is present in patients with hypertension.2
The Explore-CKD trial (NCT06150924) is a randomized, placebo-controlled, crossover phase 2 trial that evaluated the efficacy of 25 mg of lorundrostat when added to a sodium-glucose cotransporter 2 (SGLT2) inhibitor and an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker in patients with CKD. The enrolled patients had estimated glomerular filtration rates (eGFR) of 30 mL/min/1.73 m2 and albuminuria (UACR of 200–5,000 mg/g).1,2
The trial’s primary efficacy end point was the change from baseline in systolic blood pressure at week 4 in the active vs placebo treatment period. Additional exploratory end points included change from baseline in UACR and eGFR at week 4 in the active vs placebo treatment period, according to the trial investigators.1,2
The data indicated that patients treated with lorundrostat achieved reductions in systolic blood pressure and UACR of about 9.25 mm Hg and 30.51%, respectively, whereas placebo had reductions of 1.76 and 6.60%. Additionally, lorundrostat showed superior improvements in changes in eGFR (-6.78% vs -2.20%). Notably, only 5% (3 of 58) of patients receiving lorundrostat with an SGLT2 inhibitor had confirmed hyperkalemia, compared with 0 patients receiving placebo.2
The investigators noted that these data add to a growing body of evidence supporting the efficacy and safety of ASIs in addressing the underlying mechanisms of hypertension, especially in patients who also have CKD. The reduction in UACR observed in this trial is consistent with the potential of lorundrostat to have renal protective effects, said experts in a news release.2
“The Explore-CKD trial is the fourth trial showing clinically meaningful effects of lorundrostat for the treatment of hypertension. In a renally compromised hypertensive population, this trial demonstrated the benefit of lorundrostat in safely reducing both systolic blood pressure and proteinuria—a surrogate of kidney protection,” Jon Congleton, CEO of Mineralys Therapeutics, said in a news release. “Explore-CKD established that lorundrostat 25 mg once daily has a favorable clinical profile for this patient population. Along with the successful pivotal trials, Launch-HTN and Advance-HTN, and the ongoing open-label extension trial, these results comprise the core package for our planned NDA submission.”2
Serious adverse events (AEs) were reported in 2 patients (3%) during the lorundrostat treatment period and none during the placebo treatment period. Treatment-emergent AEs that led to discontinuation occurred in only 1 participant (2%) during the placebo treatment period and in 2 (3%) during the lorundrostat treatment period. Additionally, 1 patient discontinued lorundrostat treatment because of reduced eGFR-associated elevated potassium, whereas 1 discontinued treatment because of the reduction in eGFR alone.2
“Prolonged elevations in blood pressure in patients with compromised renal function can damage the small blood vessels in the kidneys, further reducing their ability to function properly,” said Matthew Weir, MD, director of the division of nephrology at the University of Maryland Medical Center and professor of medicine at the University of Maryland School of Medicine, in a news release. “The evidence generated from this trial demonstrates the unique mechanism of action and benefit of lorundrostat in lowering systolic blood pressure and UACR. Lorundrostat shows significant potential in the management of hypertension and related kidney disease.”2
