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Drug Shows Promise in Kidney Disease Trial

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In a Phase 2 trial of patients with chronic kidney disease, an experimental drug reduced albuminuria – albumin in the urine, a sign of kidney damage. The research is published in The Lancet.

Addressing kidney disease treatments

Patients with chronic kidney disease are typically treated with drugs such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB). However, their long-term use often increases levels of aldosterone, which can speed up the progression of kidney disease.

Aldosterone is a hormone that balances sodium and potassium levels to help regulate blood pressure. The drug candidate evaluated in the trial, BI 690517, is designed to inhibit aldosterone production.

“We've known for several decades that aldosterone is a major driver of inflammation and fibrosis in the kidney and also in the heart. It has just been very hard to target therapeutically,” said Dr. Katherine Tuttle, the lead author of the study and a professor of medicine at the University of Washington.

Though aldosterone inhibitors are effective at preventing the disease from progressing to kidney failure, they also come with side effects such as hyperkalemia – a dangerously high level of potassium in the blood. These considerations ultimately shaped the design of the trial.

Now, a class of drugs known as sodium–glucose cotransporter-2 (SGLT2) inhibitors has been hailed by Tuttle as one of “the biggest breakthroughs we’ve had for kidney disease in 30 years.”

SGLT2 inhibitors were initially developed to lower blood sugar but are also powerful kidney-protective drugs that can mitigate the risk of hyperkalemia.

“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 said. “Ensuring that an SGLT2 inhibitor was in the background for participants was an important design feature.”

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“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,” Tuttle continued. “And we added another medication, an SGLT2 inhibitor called empagliflozin, as background therapy for participants.”

Treatment reduced albuminuria

The researchers recruited 714 participants with kidney disease in the trial, who were randomized to receive a run-in treatment of either 8 weeks of empagliflozin or placebo.

After the run-in treatment, 586 participants went on to receive daily doses of either 3 mg, 10 mg or 20 mg of BI 690517 – or a matched placebo – for 14 weeks.

The study’s findings revealed that half of the participants treated with BI 690517 alone had a clinically meaningful reduction in albuminuria (reduced by 30% or more), and the peak response was observed for the 10 mg doses.

Additionally, 70% of participants treated with both BI 690517 and empagliflozin achieved a clinically meaningful reduction in albuminuria.

Nonetheless, researchers note that though BI 690517 treatment was also linked to higher rates of hyperkalemia, most cases required no medical intervention.

Paving the way for additional trials

The results of this study will help to inform a Phase 3 clinical trial in which BI 690517 will be evaluated in 11,000 patient participants worldwide, Tuttle explains.

“We think these are high-impact findings,” she said. “75% 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.”

Reference: Tuttle KR, Hauske SJ, Canziani ME, et al. Efficacy and safety of aldosterone synthase inhibition with and without empagliflozin for chronic kidney disease: a randomized, controlled, phase 2 trial. The Lancet. 2023. doi: 10.1016/S0140-6736(23)02408-X

This article is a rework of a press release issued by the University of Washington. Material has been edited for length and content.