Chronic Kidney Disease GAME CHANGER Cure? New Drug Shows Stunning Results in Early Trial

The article published in The Lancet assessed the efficacy and safety of BI 690517, an aldosterone synthase inhibitor, for chronic kidney disease. The trial was a multinational, randomized, controlled, phase 2 trial. The primary endpoint was the change in urine albumin to creatinine ratio (UACR) measured in first-morning void urine from baseline to the end of treatment. Dr. Tuttle's innovative research introduces a novel treatment strategy, challenging conventional approaches and offering a promising solution for kidney disease management.

Key Points

• A novel drug, BI 690517, significantly reduced albuminuria (a marker of kidney damage) in chronic kidney disease (CKD) patients when added to standard therapy (empagliflozin). The reduction was up to 39.5% compared to placebo.

• This is the first study to test this new drug class (aldosterone synthase inhibitor) on top of standard care in CKD. CKD affects over 850 million people worldwide.

• BI 690517 works by inhibiting aldosterone production, which can damage organs and worsen CKD. Existing drugs for CKD target other pathways.

• Combining BI 690517 with empagliflozin may offer additive benefits while potentially mitigating the risk of hyperkalemia (high potassium), a side effect of aldosterone inhibition.

• A large Phase III trial (EASi-KIDNEYTM) will begin in 2024 to further investigate the efficacy and safety of BI 690517. This trial will involve 11,000 participants.

• BI 690517 was generally well tolerated, with no unexpected safety signals. Dose-dependent increases in potassium were observed, but most hyperkalemia episodes did not require intervention.

• This research marks a significant advancement in CKD treatment and has the potential to improve outcomes for millions of patients.

Dr. Katherine Tuttle, the lead investigator, believes this discovery could "break the code" in combating kidney disease. Her prior research highlighted the urgency for new CKD treatments.

For decades, the mainstay of kidney disease treatment has been ACE inhibitors, originally developed for hypertension but later found to offer modest protection to organs like the kidneys. These, however, fall short in their ability to halt the inexorable progression towards kidney failure, leaving patients facing the grim spectre of dialysis or transplantation. The study, presented at the American Society of Nephrology's Kidney Week 2023, showcased remarkable reductions in albuminuria, a pivotal marker of kidney damage. What sets BI 690517 apart is its novel selective aldosterone synthase inhibition, a first-in-class approach that has the potential to reshape the landscape of chronic kidney disease (CKD) treatment.

An Innovative Tripartite Strategy

Dr. Tuttle's novel strategy incorporates a unique three-pronged approach targeting kidney damage. Integrating established drugs with the Aldosterone Synthase Inhibitor (ASI), this approach seeks to mitigate the deleterious effects of aldosterone on the kidneys. The potential of this combination, as envisioned by Dr. Tuttle, holds promise comparable to monumental medical breakthroughs.

Trials and Promising Outcomes

Unprecedented Reductions in Albuminuria

The Phase II results speak volumes: BI 690517, when administered on top of empagliflozin, an SGLT2 inhibitor, exhibited a staggering up to 39.5% reduction in albuminuria compared to the placebo. This reduction, a clear indication of kidney damage mitigation, sets a new standard in CKD therapeutics. Notably, this is the inaugural clinical trial testing this innovative treatment class against the standard of care, including empagliflozin, in individuals with CKD, a condition affecting over 850 million people globally.

Novel Mechanisms of Action

BI 690517's prowess lies in its unique mode of action, effectively and sustainably inhibiting aldosterone synthase, a key enzyme governing the final steps in aldosterone synthesis. Elevated aldosterone levels are implicated in organ damage, fostering cardio-renal-metabolic conditions such as hypertension, chronic kidney disease, or heart failure. The groundbreaking nature of this selective aldosterone synthase inhibitor marks a significant stride towards addressing critical unmet medical needs.

Positive Clinical Impact

Dr. Katherine Tuttle, Principal Study Investigator and Professor of Medicine at the University of Washington, hailed the positive and clinically relevant efficacy observed in this unique trial. The addition of BI 690517 to standard care, including SGLT2 inhibition, not only demonstrated positive kidney benefits but also hinted at a potential mitigation of hyperkalemia risk, a crucial consideration in CKD management.

Addressing Critical Unmet Needs

While acknowledging that aldosterone synthase inhibition can lead to a moderate elevation of serum potassium, the study suggests that empagliflozin's mechanism of action may play a pivotal role in mitigating the risk of hyperkalemia when used as a background therapy. This finding is of paramount clinical importance, considering that severe hyperkalemia can necessitate changes in medical therapy or even hospitalization. BI 690517, as a novel drug class, emerges as a potential game-changer in addressing this critical unmet medical need.

Key Secondary Endpoints

The Phase II trial didn't stop at showcasing reductions in albuminuria; it delved into key secondary endpoints. A clinically meaningful reduction in urine albumin creatinine ratio (UACR) was achieved by up to 70% of patients treated with BI 690517 on top of empagliflozin. These reductions, when viewed as predictive indicators, could translate into significant risk reductions for clinical kidney disease events, underscoring the profound impact of this innovative treatment approach.

Future Prospects: EASi-KIDNEYTM Trial

Looking ahead, the collaboration between Oxford Population Health and Boehringer Ingelheim is set to embark on a new frontier with the Phase III EASi-KIDNEYTM trial. With recruitment starting in 2024, this international endeavour aims to definitively test the efficacy and safety of BI 690517 on top of standard care, including empagliflozin. The sheer scale of the trial, involving around 11,000 participants with established CKD, underscores the commitment to advancing novel compounds and potential breakthroughs in cardio-renal-metabolic conditions.

Safety Profile and Tolerability

BI 690517 demonstrated a generally well-tolerated profile with no unexpected safety signals. Modest, dose-dependent increases in serum potassium levels were observed, a phenomenon mitigated in the presence of empagliflozin. Notably, hyperkalemia occurrences were consistent with the CKD population, with the majority not requiring medical intervention or BI 690517 discontinuation. This safety profile reinforces the potential of BI 690517 as a viable and well-tolerated addition to CKD treatment regimens.

Key points

1. The study assessed the efficacy and safety of BI 690517, an aldosterone synthase inhibitor, for chronic kidney disease.

2. The trial was a multinational, randomized, controlled, phase 2 trial.

3. The primary endpoint was the change in urine albumin to creatinine ratio (UACR) measured in first-morning void urine from baseline to the end of treatment.

4. BI-690517 produced similar UACR reductions when added to empagliflozin.

5. Investigator-reported hyperkalemia occurred in 10% of those in the BI 690517 3 mg group, 15% in the BI 690517 10 mg group, 18% in the BI 690517 20 mg group, and in 6% of those receiving placebo, with or without empagliflozin.

6. Adrenal insufficiency was an adverse event of special interest reported in seven of 436 study participants (2%) receiving BI 690517 and one of 147 participants (1%) receiving matched placebo.

Reference Article

Tuttle, K. R., Hauske, S. J., Canziani, M. E., Caramori, M. L., Cherney, D., Cronin, L., Heerspink, H. J. L., Hugo, C., Nangaku, M., Rotter, R. C., Silva, A., Shah, S. V., Sun, Z., Urbach, D., de Zeeuw, D., Rossing, P., & ASi in CKD group (2024). Efficacy and safety of aldosterone synthase inhibition with and without empagliflozin for chronic kidney disease: a randomised, controlled, phase 2 trial. Lancet (London, England), 403(10424), 379–390. https://doi.org/10.1016/S0140-6736(23)02408-X

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