Boehringer Ingelheim achieves major milestone in chronic kidney disease: aldosterone synthase inhibitor on top of empagliflozin delivers promising results in Phase II trial

Ingelheim, Germany, November 6, 2023 – Boehringer Ingelheim today announced promising 14-week Phase II data for BI 690517, a novel selective aldosterone synthase inhibitor (ASi). The results showed a significant reduction of albuminuria, a marker of kidney damage,² by up to 39.5% when BI 690517 was given on top of empagliflozin, a sodium glucose cotransporter (SGLT2) inhibitor, vs. placebo.¹ This is the first clinical trial testing this novel treatment class on top of standard of care including empagliflozin in people with chronic kidney disease (CKD),¹ which affects more than 850 million people worldwide.³ The findings were presented as a high-impact clinical trial at the American Society of Nephrology (ASN)’s Kidney Week 2023.¹

BI 690517 has a novel mode of action that effectively and sustainably inhibits aldosterone synthase, an enzyme that controls the final rate-limiting steps in aldosterone synthesis.^1,4 Excessive aldosterone levels cause organ damage and promote cardio-renal-metabolic conditions such as hypertension, chronic kidney disease or heart failure.⁵

“This unique trial testing a selective aldosterone synthase inhibitor on top of standard of care including SGLT2 inhibition, showed positive and clinically relevant efficacy. Using BI 690517 along with SGLT2 inhibition may offer the potential for additive kidney benefits while possibly mitigating hyperkalemia risk,” said Dr. Katherine Tuttle, Principal Study Investigator and Professor of Medicine in the Nephrology Division and Kidney Research Institute at the University of Washington, U.S. “Additional CKD treatments are urgently needed to reduce residual risks of disease progression and serious complications.”

While aldosterone synthase inhibition can lead to moderate elevation of serum potassium,⁶ this study suggests there is potential that empagliflozin’s mechanism of action can mitigate the risk of hyperkalemia when given as a background therapy.^7,8 This effect is of high clinical importance since severe hyperkalemia may lead to changes in medical therapy or hospitalization.⁹ As a novel drug class, BI 690517, on top of empagliflozin, may address this critical unmet medical need.¹

A key secondary endpoint in the Phase II trial was a clinically meaningful reduction in UACR (≥30%) which was achieved by up to 70% of patients treated with BI 690517 on top of empagliflozin.¹ Based on analyses assessing albuminuria change as a predictive indicator, these changes may translate into risk reductions for clinical kidney disease events by at least 30%.¹

“These encouraging Phase II data not only demonstrate our commitment to developing innovative and transformational treatments for people living with cardio-renal-metabolic conditions but also have the potential to decrease the global burden of these interconnected diseases,” said Carinne Brouillon, Head of Human Pharma, Boehringer Ingelheim. “With over 1 billion people worldwide affected by these conditions, the potential to help reduce the pressure on healthcare systems and patients is immense. We are proud to be leading the way in this field and are excited to move forward with the upcoming Phase III trial to further investigate the potential of this novel compound on top of standard of care including empagliflozin."

In 2024, Oxford Population Health and Boehringer Ingelheim’s new, international Phase III EASi-KIDNEY^TM trial will begin recruitment.¹ The trial aims to definitively test the efficacy and safety of BI 690517 given on top of standard of care, including empagliflozin.¹ EASi-KIDNEY^TM will recruit and follow about 11,000 participants with established CKD, at risk of kidney disease progression, using Oxford Population Health’s streamlined model.¹

BI 690517 was generally well tolerated without unexpected safety signals.¹ Dose-dependent modest increases in serum potassium levels were observed with BI 690517, which were slightly ameliorated in the presence of empagliflozin. Hyperkalemia occurred at a rate typical for a CKD population,¹ and most episodes did not require medical treatment or BI 690517 discontinuation.¹

About the trial (NCT05182840)
This Phase II, placebo-controlled, double-blind trial assessed the efficacy and safety of multiple oral doses of BI 690517 alone or on top of an SGLT2 inhibitor in people with CKD, with or without type 2 diabetes, receiving stable background therapy with an angiotensin receptor blocker (ARB) or angiotensin-converting enzyme (ACE) inhibitor.¹ Participants were first randomized (N=714) to receive either empagliflozin 10 mg or placebo for 8 weeks, then randomized a second time (N=586) to receive one of three doses of BI 690517 (3 mg, 10 mg or 20 mg) or placebo for 14 weeks.¹

The primary endpoint of the trial was to assess the efficacy of BI 690517 by measuring the percentage change in urine albumin creatinine ratio (UACR, a measure of albuminuria, which reflects kidney damage)³ from the second randomization to end of treatment.¹

The greatest placebo-corrected UACR reduction was among the participant group receiving BI 690517 10mg on top of empagliflozin.¹ There was a placebo-corrected flattening of the dose response at 10 mg among both treatment groups.¹

Participants who received both BI 690517 on top of empagliflozin experienced the following placebo-corrected changes in UACR:¹

• -9.4% (CI -27.1, 12.7) with 3mg,
• -39.5% (CI -51.8, -24.0) with 10mg,
• -33.2% (CI -46.5, -16.8) with 20mg.

These findings suggest additive efficacy when the therapies are combined.¹

Participants who received BI 690517 without empagliflozin background therapy experienced the following placebo-corrected changes in UACR:¹

• -20.3% (CI -38.6, 3.4) with 3mg,
• -37.4% (CI -52.2, -18.2) with 10mg,
• -34.9% (CI -50.7, -14.0) with 20mg.

Secondary endpoints were the proportion of patients with absolute decreases of ≥15% and ≥30% in UACR at week 14.¹ Additional endpoints included: safety and pharmacokinetic findings, change from baseline in serum potassium at week 14, change from baseline in estimated glomerular filtration rate at week 14 and changes from baseline in the plasma levels of aldosterone and its precursors.¹

About BI 690517
BI 690517 is a novel, potent, highly selective aldosterone synthase inhibitor (ASi), which is intended to slow the progression of kidney damage and to reduce cardiovascular events in people with CKD. The compound was discovered and developed by Boehringer Ingelheim and is part of its research and development portfolio in cardiovascular-renal-metabolic conditions.

About chronic kidney disease
More than 850 million people worldwide live with CKD,¹⁰ a relentless disease with no cure, which often leads to kidney failure, dialysis, or transplantation, and increases the risk of cardiovascular events and death.¹⁰ CKD is projected to progressively increase in parallel with interconnected conditions like diabetes, hypertension and obesity.^11,12

About Boehringer Ingelheim
Boehringer Ingelheim is working on breakthrough therapies that transform lives, today and for generations to come. As a leading research-driven biopharmaceutical company, the company creates value through innovation in areas of high unmet medical need. Founded in 1885 and family-owned ever since, Boehringer Ingelheim takes a long-term, sustainable perspective. More than 53,000 employees serve over 130 markets in the two business units Human Pharma and Animal Health. Learn more at www.boehringer-ingelheim.com

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References
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¹Tuttle KR, Hauske SJ, Canziani ME, et al. Aldosterone synthase inhibition with or without background sodium-glucose cotransporter-2 inhibition in CKD: a Phase II clinical trial. Oral presentation at: Ann Mtg of the American Society of Nephrology 2023. Abstract number FR-OR111.
²Jongs N, et al. Lancet Diabetes Endocrinol 2021;9:755-66.
³Li P, et al. Braz J Med Biol Res. 2020; 53(3): e9614.
⁴Xing Y, et al. Endocrinology. 2011;152(3):751-63.
⁵Otsuka, H. et al. Int J Mol Sci. 2023; 24(6): 5370.
⁶Rodan, Aylin R. Pediatric Nephrology. 2017;32(7):1109-1121.
⁷Ferreira JP, et al. J Am Coll Cardiol. 2021;77:1397–1407.
⁸Wanner C, et al. N Engl J Med. 2016;375:323–334.
⁹Larivée, NL et al. Cardiol Ther. 2023;12:35–63.
¹⁰Li P, et al. Braz J Med Biol Res. 2020; 53(3): e9614.
¹¹Evans M, et al. Adv Ther 2022;39:33-43.
¹²Braun, L. et al. Int J Nephrol Renovasc. Dis 2012;5:151-63.