Kerendia (Finerenone): First Non-Steroidal, Selective MRA Demonstrating Positive Renal and Cardiovascular Outcomes in CKD Patients with Type 2 Diabetes

Kidney (Image source:diabetes.co.uk）

Bayer(Bayer) recently announced that the U.S. Food and Drug Administration (FDA) has approved Kerendia (finerenone) for the treatment of chronic kidney disease (CKD) with type 2Diabetesadult patients with (T2D), to reduce the risk of sustained decline in estimated glomerular filtration rate (eGFR), end-stage kidney disease (ESKD), cardiovascular death, non-fatal myocardial infarction, and hospitalization for heart failure. Kerendia was approved via the Priority Review program. Currently, the drug is also under regulatory review in the European Union, China, and several other countries.

Kerendia is a first-in-class, nonsteroidal, selective mineralocorticoid receptor antagonist (MRA) that reduces the harmful effects of mineralocorticoid receptor (MR) overactivation. MR overactivation can lead to inflammation and fibrosis, which are key drivers of CKD progression and cardiac damage.

Notably, Kerendia is the first non-steroidal selective mineralocorticoid receptor antagonist (MRA) to demonstrate positive renal and cardiovascular outcomes in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D). Despite guideline-directed medical therapy, many patients with CKD and T2D still progress to loss of kidney function and remain at high risk for cardiovascular events. Kerendia’s mechanism of action differs from existing therapies; by blocking the overactivation of the mineralocorticoid receptor (MR), the drug directly targets inflammation and fibrosis to slow disease progression.

  FDAThe approval of Kerendia is based on the positive results from the pivotal Phase 3 FIDELIO-DKD study. The relevant data were presented at the American Society of Nephrology (ASN) Kidney Week 2020 and published in *The New England Journal of Medicine* (*NEJM*) in October 2020. For details, see:Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes。

     FIDELIO-DKDPrincipal Investigator of the study, University of Chicago School of MedicineGeorge L. BakrisThe professor stated:“Worldwide, there are over1.6hundred millionCKDMergeT2DPatients. Even when blood glucose levels and blood pressure are well controlled, patients still haveCKDRisk of progression. This underscores a high medical need for early intervention to prevent further end-organ damage and premature death by slowing the rate of renal function decline and reducing cardiovascular risk in patients.fineenoneThe approval provides a new pathway, by addressingMROveractivation (CKDkey drivers of progression) to protect patients from further renal damage, an unmet need that currently available therapies have yet to address.”

finerenoneChemical structure (Image source:newdrugapprovals.org）

      FIDELIO-DKDResearch inCKDComplicated byT2Dwas conducted in patients, and evaluatedfinerenoneEfficacy and safety versus placebo.2Patients in both groups received standard of care, including glucose-lowering therapy and the maximally tolerated dose of renin.-Angiotensin system (RAS) blockade therapy, such as angiotensin-converting enzyme (ACE) inhibitor or angiotensinIIreceptor blocker (ARB）。

The results demonstrated that the study met its primary endpoint: in combination with standard of care, finerenone significantly reduced the risk of the composite primary endpoint of CKD progression, kidney failure, and renal death compared with placebo. Specifically, over a median follow-up of 2.6 years, finerenone significantly reduced the composite risk of first occurrence of kidney failure, a sustained decline in estimated glomerular filtration rate (eGFR) of ≥40% from baseline for at least 4 weeks, and renal death by 18% compared with placebo (HR = 0.82; 95% CI: 0.73–0.93; p = 0.0014). In prespecified subgroups, the effect of finerenone on the primary outcome was largely consistent, and the treatment benefit was sustained throughout the study period.

Furthermore, over a median follow-up of 2.6 years, compared with placebo, finerenone also significantly reduced the risk of key secondary endpoints: cardiovascular death, nonfatal myocardial infarction, and nonfatalStrokeor heart failure hospitalization, the composite risk was reduced by 14% (relative risk reduction, HR=0.86 [95% CI: 0.75–0.99; p=0.0339]).

In this study,finerenonewas well tolerated, with a safety profile consistent with that observed in previous studies. Overall treatment-related adverse events and serious adverse events were2Similar between groups. Most adverse events were mild or moderate.finerenoneThe group had a lower incidence of serious adverse events compared with the placebo group (31.9% vs 34.3%）higher incidence of hyperkalemia-related adverse events（18.3% vs 9%），2The incidence of hyperkalemia-related serious adverse events in both groups was relatively low (1.6% vs 0.4%），2No hyperkalemia-related deaths occurred in any group.finerenoneThe proportion of patients in the group who discontinued treatment due to hyperkalemia was2.0%, while the placebo group was0.9%。

FIDELIO-DKDClinical Data

Chronic Kidney Disease (CKD) isOne of the most common complications of diabetes, it is also an independent risk factor for cardiovascular disease. Among all patients with type 2 diabetes, approximately 40% will develop CKD. CKD is a leading cause of end-stage renal disease and renal failure; in advanced stages, patients may require dialysis or kidney transplantation to survive. Over a 10-year period, patients with type 2 diabetes and CKD are three times more likely to die from cardiovascular-related diseases than those with type 2 diabetes alone. It is well known that in patients with type 2 diabetes and CKD, mineralocorticoid receptor overactivation...can trigger harmful processes (e.g., inflammation and fibrosis) in the kidneys and heart. Globally,2in patients with type diabetesCKDis the most common cause of renal failure.

        finerenone IIIPhase clinical trial is the largest to date.CKD IIIPhase clinical trial. The project is2consisting of studies, with enrollment from sites worldwide1.310,000 Cases with a Wide Range of SeverityCKDdiseaseT2Dpatients, including those with early renal impairment and more advanced renal disease. This study aims to evaluatefinerenoneversus placebo, each in combination with standard of care, on renal and cardiovascular (CV）impact on prognosis.

finerenoneMechanism of Action (Image source:researchgate.net）

      FIDELIO-DKD（finerenoneReducing renal failure and disease progression in diabetic nephropathy) is a randomized, double-blind, placebo-controlled, parallel-group, multicenter, event-drivenIIIphase study, which enrolled participants from around the world48countries1000Multi-Site Appointments5700cases withCKDofT2DPatients. In the study, these patients were randomized to receive once-daily oral administration10mgor20mgoffinerenoneor placebo, while receiving standard of care, including glucose-lowering therapy and maximally tolerated doses of renin-Angiotensin System (RAS) blockers, such as angiotensin-converting enzyme (ACE) inhibitor or angiotensinIIreceptor blocker (ARB). The study has met the primary endpoint.

       FIGARO-DKD（finerenone... reducing cardiovascular morbidity and mortality in diabetic kidney disease) study is still ongoing; this study is being conducted in Europe, Japan, China, the United States, and other48countries enrolled approximately7400cases accompanied byCKDofT2DPatient, under investigationfinerenonerespectively combined with standard of care versus placebo plus standard of care in reducingCVEfficacy and safety in terms of morbidity and mortality.

Additionally, Bayer also launchedFINEARTS-HFstudy, this is a multicenter, randomized, double-blind, placebo-controlledIIIPhase study, will be conducted at over5500Case: Left Ventricular Ejection Fraction≥40%symptomatic heart failure (HF) Patient (New York Heart AssociationII-IVGrade) investigated infinerenoneversus placebo. The primary objective of the study is to demonstratefinerenonein reducingCVDeath and Overall (First and Recurrent)HFEvents (defined as heart failure or emergencyHFhospital visits) in terms of the incidence of the composite endpoint was superior to placebo.