Results of a clinical trial led by researchers at the University of Washington School of Medicine show an experimental kidney disease drug candidate inhibited the levels of the damaging hormone aldosterone. These findings, published in The Lancet, showed that the drug, BI 690517, produced significant reductions in albumin in the urine—called albuminuria, a biomarker of kidney damage—in 50 percent of the patients enrolled. When combined with current standard-of-care medication, 70 percent of participants exhibited a significant reduction in albuminuria.
Aldosterone is a hormone that balance sodium and potassium levels in the body to help regulate blood pressure, but too much of it accelerate the progression of kidney disease. According the lead author Katherine Tuttle, MD, the challenge to finding a more effective treatments for kidney disease is preventing serious side effects. Current therapies include angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) which have been shown to reduce levels of aldosterone. While these reduce kidney inflammation and prevent the progression of kidney disease, they can also, over time, dangerously increase blood potassium levels—a state referred to as hyperkalemia.
Tuttle and team therefore sought to find ways to both inhibit aldosterone while preventing hyperkalemia. Describing the trial, Tuttle noted: “Participants had to be on an ACE or an ARB at a maximally tolerated dose for at least four weeks before they could go into the study and we added another medication, an SGLT2 inhibitor called empagliflozin, as background therapy for participants.”
SGLT2 (sodium-glucose cotransporter-2) inhibitors were initially designed at drugs to lower blood sugar, but they have also been identified as drugs that protect the kidneys—another important benefit is these drug also lower the risk of a patient developing hyperkalemia, a finding Tuttle calls one of “the biggest breakthroughs we’ve had for kidney disease in 30 years.
“That gave us the opportunity to test BI 690517 for efficacy at increasing the protection of kidneys and also to reduce the major side effect that had limited the use of aldosterone-inhibiting agents,” Tuttle continued. “Ensuring that an SGLT2 inhibitor was in the background for participants was an important design feature.”
The trial enrolled 714 patients diagnosed with kidney disease and were randomized into either an initial eight-week therapy of the SGLT2 diabetes drug empagliflozin or a matched placebo. Subsequently, 586 patients were randomly assigned to receive BI 690517 at a daily dose of 3 mg, 10 mg, or 20 mg, or a matched placebo for 14 weeks.
Albuminuria reduction was used to measure treatment efficacy and the results showed that more than half of the participants who received the BI 690517 alone exhibited a albuminuria level reductions of 30%, with the best results in those receiving the 10 mg does. But it also showed that 70% of participants who received both BI 690517 and empagliflozin achieved a clinically meaningful albuminuria reduction. While the use of BI 690517 was also associated with higher rates of hyperkalemia compared with placebo, most cases did not require medical intervention.
These results will now be used to inform the design of a Phase III trial that plans to enroll 11,000 patients around the world.
“We think these are high-impact findings,” Tuttle said. “Seventy-five percent of all people on dialysis have diabetes or hypertensive kidney disease, and these agents—if we can get it right in terms of awareness and access and detection at a stage where it’s treatable—might make dialysis almost obsolete. This is in reach.”
