What clinical trials have been conducted for Finerenone?

Introduction to Finerenone
Finerenone is an investigational, non‐steroidal, selective mineralocorticoid receptor (MR) antagonist developed for the management of conditions characterized by MR overactivation such as chronic kidney disease (CKD) and type 2 diabetes (T2D) as well as certain cardiovascular conditions. Its molecular design distinguishes it from steroidal MR antagonists like spironolactone and eplerenone by providing improved receptor selectivity and a different tissue distribution, which may translate into a better adverse effect profile.

Overview and Mechanism of Action
Finerenone works by selectively inhibiting the mineralocorticoid receptor overactivation that plays a key role in driving inflammation, fibrosis, and ultimately the progression of kidney and cardiovascular damage. Unlike classical steroidal antagonists, finerenone does not significantly interact with androgen, progesterone, or estrogen receptors, which reduces the likelihood of hormonal side effects. The overactivation of MR in tissues such as the heart, kidney, and blood vessels induces deleterious cascades that lead to structural tissue remodeling and dysfunction. By blocking these receptors, finerenone modulates sodium reabsorption and suppresses the inflammatory and fibrotic responses, thereby reducing the risk of adverse clinical outcomes in susceptible populations.

Therapeutic Uses and Indications
The principal therapeutic use of finerenone is in patients with CKD associated with T2D, a population at high risk for both renal and cardiovascular events. Clinical trials have demonstrated that finerenone slows the progression of kidney disease—including reductions in albuminuria and sustained decreases in estimated glomerular filtration rate (eGFR)—while also reducing events such as cardiovascular death, myocardial infarction, and hospitalization for heart failure. Additional potential indications under investigation include its use in heart failure populations beyond the common CKD/T2D cohorts, such as patients with heart failure and preserved ejection fraction (HFpEF).

Clinical Trials Overview
Clinical trials are structured studies that follow a phased approach to investigate the pharmacokinetics, safety, efficacy, and overall clinical utility of a new therapeutic intervention. They serve as the backbone for translating promising molecular candidates into treatment options in clinical practice.

Phases of Clinical Trials
Clinical trials typically progress in several phases. Phase I studies are designed to understand the drug’s pharmacokinetic and pharmacodynamic properties in healthy volunteers, ensuring that the compound is safe for further evaluation. Phase II trials focus on evaluating efficacy and confirming optimal dosing while providing additional safety data. Finally, Phase III trials involve large patient populations to confirm the drug’s efficacy in a broader clinical setting and determine its risk–benefit profile compared to placebo or standard therapy.

Importance of Clinical Trials in Drug Development
Robust clinical trials are essential for the development of any novel drug. They not only test the safety and tolerability of the drug in controlled environments but also assess its therapeutic impact on disease progression and symptom alleviation under real‐world conditions. Through a rigorous stepwise approach, these trials help refine dosing regimens, identify adverse effects early on, and provide a comprehensive picture of the drug’s clinical efficacy before regulatory authorities grant marketing approval. In the case of finerenone, the extensive clinical trial program has been critical in shaping our understanding of its role in slowing CKD progression, reducing cardiovascular events, and potentially expanding its use to other indications such as heart failure.

Conducted Clinical Trials for Finerenone
The clinical trial program for finerenone has been extensive, covering all phases from early pharmacokinetic/personality assessments to large-scale pivotal studies. The conducted clinical trials have been designed to explore the drug’s pharmacological characteristics, its efficacy in reducing kidney and cardiovascular endpoints, and its safety profile in diverse patient populations.

Phase I Trials
Phase I studies have been essential in characterizing the pharmacokinetics and absorption characteristics of finerenone. These studies involved healthy male volunteers to ensure a controlled environment for initial dosing evaluations.

One key study investigated the dose linearity across a range of doses (from 1.25 mg up to 20 mg) and evaluated how food intake and co-administration of medications, such as proton-pump inhibitors (e.g., omeprazole) and antacids, affected the pharmacokinetics of finerenone. The results demonstrated that finerenone is rapidly absorbed with a t_max between 0.50 and 0.75 hours, and both the area under the concentration–time curve (AUC) and peak plasma concentration (C_max) increased proportionally with dose. In another Phase I study, the absolute bioavailability of finerenone was quantified at approximately 43.5%, indicating that first-pass metabolism in the gut wall and liver plays a significant role in the drug’s disposition. These early results provided a strong foundation for determining the appropriate doses for subsequent Phase II and III studies while clarifying drug–drug interactions that might influence finerenone’s clinical use.

Phase II Trials
Phase II trials for finerenone have been designed to assess preliminary efficacy observations and optimal dosing while providing further safety data in patient populations that represent the intended indication group. While the Phase II studies are not as widely detailed as the later pivotal trials in the available synapse-hosted references, early-phase investigations such as ARTS-DN and ARTS-HF played a significant role. The ARTS (A Randomized, double-blind, placebo-controlled, study of Finerenone) studies helped in determining the efficacy of finerenone in reducing albuminuria in patients with diabetic kidney disease and offered insights into its potential cardiovascular benefits, including mitigating heart failure-related symptoms. Although explicit reference numbers for ARTS studies were not provided in the current set of references, the results of these dose-ranging studies contributed critical information leading to the dose selection for Phase III trials. These Phase II studies also evaluated complementary endpoints such as changes in serum potassium—which is an important safety marker given the mechanism of MR antagonism—alongside the primary efficacy endpoints related to kidney function.

Phase III Trials
Phase III represents the most extensive evaluation of finerenone and is pivotal for its regulatory approval. The Phase III clinical trial program for finerenone has included several large, multicenter, randomized controlled trials that rigorously evaluated both renal and cardiovascular endpoints in patients with CKD associated with T2D. These trials include:

1. FIDELIO-DKD (Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease):
FIDELIO-DKD is one of the landmark Phase III studies that enrolled approximately 5,700 patients with CKD and T2D. The trial was designed to evaluate the efficacy of finerenone in reducing the risk of kidney failure, sustained eGFR decline (typically a ≥40% reduction from baseline), or death from renal causes. The outcomes demonstrated that finerenone significantly reduced the composite renal endpoint compared to placebo. Notably, the reduction in albuminuria and the decline of kidney function evidenced the drug’s renoprotective benefits. The study’s results were a cornerstone for the subsequent approval of finerenone as an agent to delay CKD progression in this high-risk population.

2. FIGARO-DKD (Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease):
FIGARO-DKD, another key Phase III trial, enrolled approximately 7,400 patients with less-advanced CKD associated with T2D and focused primarily on cardiovascular outcomes. The trial showed that finerenone significantly reduced cardiovascular events such as cardiovascular death, nonfatal myocardial infarction, and hospitalization for heart failure. This trial complemented the findings of FIDELIO-DKD by demonstrating benefits not only in kidney parameters but also in reducing the burden of cardiovascular disease in diabetic populations. The pooled analysis from FIDELIO-DKD and FIGARO-DKD, often referenced as FIDELITY, further reinforced the cardiorenal benefits of finerenone.

3. FINEARTS-HF (FINerenone trial to investigate Efficacy and sAfety superioR to placebo in paTientS with Heart Failure):
The FINEARTS-HF trial is a Phase III study specifically designed to evaluate the efficacy and safety of finerenone in patients with symptomatic heart failure with a left ventricular ejection fraction (LVEF) ≥40%. Enrolling more than 5,500 patients across multiple geographic regions, FINEARTS-HF aims to provide robust data on cardiovascular death and total heart failure events (including hospitalizations and urgent visits). This trial builds upon earlier investigations and seeks to extend the potential use of finerenone beyond the CKD and T2D populations, targeting a broader heart failure cohort.

4. Additional Trials and Exploratory Studies:
Beyond the two pivotal Phase III studies, several additional trials have been conducted or are ongoing to examine specific aspects of finerenone’s profile. For example:
- A fasting and postprandial bioequivalence study of finerenone tablets was conducted. These bioequivalence studies are crucial as they ensure the consistency of the drug formulation and the validity of the pharmacokinetic parameters across different feeding conditions in healthy subjects.
- A study on the bioequivalence of finerenone tablets in Chinese healthy adult subjects is another example indicating a drive for global clinical development and ensuring that the pharmacological profile is consistent across ethnic groups.
- Additionally, some trials have extended the investigation of finerenone to less traditional populations such as patients with non-diabetic glomerulonephritis and observational studies looking at its safety in kidney transplant recipients.
- There are also trials focusing on cost-effectiveness and simulation models of finerenone in combination therapeutic regimens for patients with T2D and CKD.
- Real-world registries and observational studies, for example in Indian populations with CKD and T2D, have been undertaken to provide additional data on the tolerability and efficacy of finerenone in routine practice.

These Phase III trials, among the largest and most rigorously designed in their class, have collectively contributed to a comprehensive understanding of finerenone’s effects. They have provided extensive evidence on its ability to attenuate kidney function decline, reduce cardiovascular events, and do so with manageable safety concerns, paving the way for regulatory approvals in multiple jurisdictions.

Outcomes and Implications

Efficacy Results
The clinical efficacy of finerenone has been established through multiple large-scale Phase III studies. In FIDELIO-DKD, finerenone reduced the composite renal endpoint—including kidney failure, sustained eGFR decline by at least 40%, or death from renal causes—by approximately 18% compared to placebo. This renoprotective effect was primarily driven by a reduction in the sustained decline of kidney function, with a corresponding decrease in albuminuria observed early in the trial.
In FIGARO-DKD, the cardiovascular benefits of finerenone were apparent. The trial demonstrated a statistically significant reduction in the composite cardiovascular endpoint, which included cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure. The pooled analysis under the FIDELITY program further consolidated these findings by showing a reduction in both renal and cardiovascular outcomes, confirming the dual beneficial role of finerenone in high-risk patient populations with CKD associated with T2D.
Furthermore, early data from the FINEARTS-HF trial suggest a trend toward reduced heart failure hospitalization and cardiovascular death in symptomatic heart failure patients, although some endpoints require further confirmation with complete trial data.

Safety and Adverse Effects
Safety has been a critical aspect of finerenone’s clinical development. Across the various trials, the most frequently reported adverse reaction has been hyperkalemia, which was more pronounced in the finerenone groups compared to placebo (with hyperkalemia-related adverse events reported in approximately 18.3% of finerenone-treated patients versus 9% in placebo groups in pivotal trials). Despite the increased incidence of hyperkalemia, the discontinuation rates due to this side effect remained low (around 2.3% in finerenone-treated patients versus 0.9% in the placebo group), indicating that the adverse effect was manageable with appropriate monitoring and dose adjustments.
Additional safety data from the Phase I and II studies confirmed that finerenone has a predictable pharmacokinetic profile with a low potential for significant drug–drug interactions and an acceptable tolerability profile, which further supported its progression into large-scale Phase III trials. Moreover, the trials have also confirmed that finerenone lacks clinically significant interactions with other hormonal receptors, reducing the risk of off-target adverse events commonly associated with other mineralocorticoid receptor antagonists.

Regulatory Approvals and Future Directions
The compelling evidence generated from the extensive clinical trial program has led to regulatory approvals in several regions. Based on the results of both FIDELIO-DKD and FIGARO-DKD, finerenone (marketed as Kerendia®) has been approved for reducing the risk of CKD progression and cardiovascular events in patients with CKD associated with T2D. Such approvals mark a significant milestone in the management of diabetic kidney disease and provide physicians with a valuable tool to slow the progression of renal impairment while simultaneously addressing cardiovascular risks.
Looking forward, the results from the FINEARTS-HF trial may expand the potential indications of finerenone to include broader heart failure populations beyond those with CKD and T2D. Ongoing studies evaluating finerenone’s effectiveness in other renal pathologies (e.g., non-diabetic glomerulonephritis) and its real-world performance in various ethnic groups underscore the commitment to refining dosing algorithms and expanding clinical use. Additionally, post hoc analyses and modeling studies investigating cost-effectiveness and combination therapies further strengthen the therapeutic positioning of finerenone in comprehensive cardiorenal care.

Conclusion
In summary, a robust and diverse clinical trial program has been conducted for finerenone, spanning from Phase I investigations focused on pharmacokinetic profiling to large-scale Phase III studies that conclusively demonstrated its renoprotective and cardioprotective efficacy. Phase I studies established essential pharmacological characteristics such as dose linearity, bioavailability, and the effect of food and drug interactions. Phase II trials, although less detailed in the available synapse sources, were key in refining the dosing strategy and demonstrating preliminary clinical efficacy and safety in reducing albuminuria and stabilizing kidney function in patients with diabetic kidney disease.
The cornerstone of finerenone’s clinical evaluation is represented by the major Phase III trials—FIDELIO-DKD and FIGARO-DKD. These studies enrolled a combined patient population exceeding 13,000 individuals with CKD and T2D, thereby establishing the ability of finerenone to significantly reduce renal and cardiovascular adverse events. In addition, the FINEARTS-HF trial is further expanding the clinical understanding of finerenone by evaluating its utility in heart failure patients with preserved ejection fraction.
Across all trials, the efficacy results have been impressive, with notable reductions in key endpoints such as a 40% decline in eGFR, kidney failure, and a composite of cardiovascular events. The safety profile has been generally favorable despite the predictable increase in hyperkalemia-related events, which remain manageable through careful monitoring.
Ultimately, the extensive clinical data have led to regulatory approvals in multiple regions and set the stage for future studies aimed at further broadening the clinical utility of finerenone. Future directions include validating its efficacy in additional populations (such as non-diabetic kidney diseases and broader heart failure indications), optimizing combination therapy with other agents (including SGLT-2 inhibitors), and exploring its cost-effectiveness and long-term benefits in real-world clinical practice.

In conclusion, the systematic progression from early-phase pharmacokinetic studies to extensive Phase III trials underscores the scientific rigor behind finerenone’s development. This polyphasic clinical evaluation not only affirms its efficacy and safety profile but also provides a comprehensive framework for its future role as an essential therapeutic option in managing CKD, T2D, and possibly heart failure. The clinical trial data for finerenone, sourced primarily from structured and reliable studies hosted by synapse, exemplify how methodical clinical investigation can transform novel molecular insights into approved and effective therapies.