Vicadrostat (BI 690517): A Comprehensive Profile of an Investigational Aldosterone Synthase Inhibitor

I. Introduction

Vicadrostat, also known by its development code BI 690517, is an investigational small molecule pharmaceutical agent developed by Boehringer Ingelheim.[1] It is currently undergoing extensive clinical evaluation for its therapeutic potential in managing chronic kidney disease (CKD) and heart failure, particularly heart failure with preserved ejection fraction (HFpEF).[2] As a novel, selective aldosterone synthase inhibitor (ASi), Vicadrostat represents a targeted approach to mitigating the deleterious effects of excessive aldosterone, a key hormone in the renin-angiotensin-aldosterone system (RAAS) implicated in the pathophysiology of various cardiovascular, renal, and metabolic disorders.[3] This report provides a comprehensive overview of Vicadrostat, detailing its chemical properties, mechanism of action, pharmacokinetic profile, clinical development program, safety and tolerability, and its potential positioning within the evolving therapeutic landscape for cardiorenal diseases. The information compiled is based on publicly available data from clinical trial registries, scientific publications, and regulatory sources.

II. Drug Identity and General Characteristics

A. Nomenclature and Identification Codes

Vicadrostat is the official non-proprietary name (International Nonproprietary Name - INN) for the compound BI 690517.[3] It is systematically identified by the Chemical Abstracts Service (CAS) Registry Number 1868065-21-7.[7] In chemical databases, it is also referenced by its PubChem Compound ID (CID) 118676295 [9] and InChIKey MCVIVPZYYMNCAW-OAHLLOKOSA-N.[6] These unique identifiers are crucial for unambiguous referencing in scientific literature and regulatory documentation.

B. Chemical Structure and Properties

Vicadrostat is a non-steroidal small molecule.[5] Its chemical formula is C15​H12​ClN3​O3​, corresponding to a molecular weight of approximately 317.73 g/mol.[6] The systematic chemical name is 2-Chloro-4-imidazol-3(4H)-yl]benzonitrile.[6] Its structure incorporates a pyrano[3,4-d]imidazole core linked to a substituted benzonitrile moiety. The SMILES (Simplified Molecular Input Line Entry System) string is C[C@@]1(Cc2c(C(=O)O1)n(cn2)-c3ccc(C#N)c(c3)Cl)CO.[6]

The non-steroidal nature of Vicadrostat is a significant characteristic. Steroidal aldosterone antagonists, such as spironolactone and eplerenone, while effective, can interact with other steroid hormone receptors (e.g., androgen and progesterone receptors) due to their structural similarity to endogenous steroid hormones. This can lead to undesirable side effects like gynecomastia, menstrual irregularities, and impotence. Vicadrostat's distinct non-steroidal chemical structure, based on a pyrano[3,4-d]imidazole framework, is designed to avoid these steroid receptor-mediated off-target effects, potentially offering a more favorable tolerability profile, which could enhance patient adherence in chronic treatment settings.

Table 1: Vicadrostat: Key Chemical and Physical Properties

Property	Value	Reference(s)
Official Name	Vicadrostat	6
Alternative Name/Code	BI 690517	2
CAS Number	1868065-21-7	7
Molecular Formula	C15​H12​ClN3​O3​	6
Molecular Weight	317.73 g/mol	6
Key Structural Features	Non-steroidal, pyrano[3,4-d]imidazole derivative, benzonitrile	5
PubChem CID	118676295	9
InChIKey	MCVIVPZYYMNCAW-OAHLLOKOSA-N	6

C. Administration Route and Dosage Forms

Vicadrostat is primarily being developed for oral administration, typically in the form of film-coated tablets.[2] This route is preferred for chronic conditions like CKD and heart failure due to patient convenience and compliance. Clinical trials have investigated various oral doses, including 3 mg, 10 mg, and 40 mg once daily.[13] Phase 1 studies explored doses up to 80 mg.[14] The 10 mg once-daily dose appears to be a common dosage in later-phase studies, such as the EASi-KIDNEY trial.[16]

Interestingly, an intravenous administration route was also reported as being under development at one stage.[2] While the current focus for Phase III trials is clearly on the oral tablet formulation for chronic outpatient therapy, the prior existence of an intravenous formulation suggests a comprehensive early development program. Such formulations are often utilized in Phase I studies to determine absolute bioavailability (by comparing intravenous to oral drug exposure) or for pharmacokinetic/pharmacodynamic assessments requiring precise control over drug delivery and systemic concentrations. This thorough early characterization, even if the intravenous route is not pursued for market, can provide valuable foundational data for the drug's overall development.

III. Mechanism of Action and Pharmacological Effects

A. Detailed Explanation of Aldosterone Synthase Inhibition

Vicadrostat functions as an aldosterone synthase inhibitor (ASi).[1] Its primary pharmacological action is to target and inhibit the enzyme aldosterone synthase, also known as cytochrome P450 11B2 (CYP11B2).[5] This enzyme is predominantly located in the zona glomerulosa of the adrenal cortex and is responsible for catalyzing the final and rate-limiting steps in aldosterone biosynthesis, specifically the conversion of 11-deoxycorticosterone to corticosterone, then to 18-hydroxycorticosterone, and finally to aldosterone.[3] By inhibiting CYP11B2, Vicadrostat effectively reduces the de novo production of aldosterone.[3] The reported half-maximal inhibitory concentration (IC50​) of Vicadrostat for aldosterone synthase is 48 nM, indicating potent enzymatic inhibition.[7] Reduced aldosterone levels are anticipated to ameliorate the hormone's detrimental contributions to inflammation, fibrosis, sodium and water retention, and potassium excretion, which are implicated in the progression of cardiovascular and renal diseases.[3]

B. Selectivity and Impact on the Renin-Angiotensin-Aldosterone System (RAAS)

A critical feature of Vicadrostat is its high selectivity as an ASi.[1] It exhibits a reported 250-fold greater affinity for aldosterone synthase (CYP11B2) compared to cortisol synthase (11β-hydroxylase or CYP11B1), the enzyme responsible for cortisol production in the adrenal gland.[5] This high degree of selectivity is paramount for minimizing off-target hormonal disruptions, particularly the suppression of cortisol synthesis, which could lead to adrenal insufficiency. Indeed, Phase II trial data indicated no significant alteration in cortisol levels with Vicadrostat treatment.[5] Although cortisol levels are carefully monitored in ongoing large clinical trials like EASi-KIDNEY, symptomatic hypocortisolism was not reported as a concern in approximately 700 CKD patients treated in Phase II studies.[17] This superior selectivity over CYP11B1 addresses a significant historical challenge in the development of ASi drugs, where lack of selectivity often led to unacceptable adverse effects related to impaired cortisol production, making Vicadrostat a more viable therapeutic candidate.

By diminishing aldosterone production, Vicadrostat directly intervenes in the RAAS pathway. Even with the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs), a phenomenon known as "aldosterone breakthrough" can occur, where aldosterone levels rise again over time, contributing to ongoing cardiorenal damage.[18] Vicadrostat's mechanism offers a way to target this residual aldosterone-driven risk.

C. Key Pharmacodynamic Outcomes

Clinical studies have demonstrated several key pharmacodynamic effects of Vicadrostat, confirming its mechanism of action and therapeutic potential:

• Aldosterone Suppression: Phase 1 studies in healthy male volunteers consistently showed that Vicadrostat administration led to a rapid and marked decrease in plasma aldosterone concentrations, typically observed 1–2 hours post-dose. This suppression was dose-dependent, with more pronounced reductions at higher Vicadrostat doses.[14] Similar aldosterone suppression was confirmed in Phase I trials involving patients with diabetes and albuminuric CKD.[13] This consistent and dose-dependent reduction in plasma aldosterone provides robust evidence of target engagement in vivo and forms the mechanistic foundation for the anticipated downstream clinical benefits.
• Urine Albumin-to-Creatinine Ratio (UACR) Reduction: Reduction in UACR is a critical surrogate marker for improved renal outcomes in CKD.
• Phase II trials in patients with albuminuric CKD demonstrated that Vicadrostat, typically at a 10 mg daily dose, reduced UACR by approximately 40% compared to placebo, both as monotherapy and when co-administered with the SGLT2 inhibitor empagliflozin.[5]
• Notably, when Vicadrostat was combined with empagliflozin, the UACR reduction appeared synergistic, reaching up to approximately 61%.[5] Other reports indicate that the combination reduced albuminuria by up to 40% [21], and that up to 70% of participants achieved a clinically meaningful UACR reduction (defined as ≥30%) when Vicadrostat was added to empagliflozin therapy.[22] This synergistic effect suggests that targeting two distinct pathophysiological pathways—aldosterone production by Vicadrostat and SGLT2-mediated effects by empagliflozin—offers more comprehensive renal protection than either agent alone. This observation strongly supports the current therapeutic paradigm shift towards multi-drug regimens for complex, multifactorial diseases like CKD and provides a compelling rationale for the large-scale combination therapy trials.
• Blood Pressure Modulation: Aldosterone contributes to hypertension through sodium and water retention and vascular effects.
• Aldosterone synthase inhibitors as a class have been shown to reduce office systolic blood pressure by approximately 6.3 mmHg and diastolic blood pressure by approximately 2.2 mmHg in hypertensive patients.[23]
• Specifically, the combination of Vicadrostat and empagliflozin was reported to lower systolic blood pressure by 7.8 mmHg in Phase II, a reduction greater than that observed with either agent alone.[5] Consequently, blood pressure is routinely monitored in clinical trials involving Vicadrostat.[20]

These pharmacodynamic effects—aldosterone suppression, UACR reduction, and blood pressure lowering—are key indicators of Vicadrostat's therapeutic potential in cardiorenal diseases.

IV. Pharmacokinetics

Understanding the absorption, distribution, metabolism, and excretion (ADME) properties of Vicadrostat is essential for optimizing dosing regimens, predicting potential drug interactions, and interpreting variability in patient responses.

A. Absorption, Distribution, Metabolism, and Excretion (ADME)

• Absorption: Following oral administration, plasma exposure to Vicadrostat, as measured by the area under the concentration-time curve (AUC), increases in a dose-dependent manner.14 The median time to reach maximum plasma concentration (Tmax) ranges from 0.50 to 1.75 hours, indicating relatively rapid absorption from the gastrointestinal tract.14 The effect of food on Vicadrostat absorption has been studied. Administration with a standardized high-fat, high-calorie meal was found to reduce the rate of absorption (i.e., Tmax was delayed), but it did not significantly alter the overall extent of absorption (i.e., AUC remained largely unchanged).14 This finding has practical implications for patient dosing, suggesting that Vicadrostat can be taken with or without food without a clinically significant impact on total drug exposure, which can simplify dosing instructions and improve patient adherence. While taking it on an empty stomach might lead to a slightly faster onset of peak concentrations, this is generally not considered clinically critical for a maintenance medication used for chronic conditions.
• Metabolism: Vicadrostat is primarily metabolized via glucuronidation, a Phase II metabolic pathway. Specifically, it is conjugated by the uridine 5′-diphosphate glucuronyltransferase (UGT) enzymes UGT2B7 and UGT2B4.17 Metabolism predominantly through UGT pathways, rather than Cytochrome P450 (CYP) enzyme systems (which are not highlighted as major metabolic routes for Vicadrostat in the available information), may confer a lower potential for many common drug-drug interactions. CYP enzymes, such as CYP3A4, CYP2D6, and CYP2C9, are responsible for the metabolism of a vast number of xenobiotics and are frequently implicated in clinically significant drug interactions. A metabolic profile less reliant on these CYP pathways could be a notable advantage for Vicadrostat, particularly in patient populations with CKD or heart failure who often present with multiple comorbidities and require polypharmacy. Importantly, exploratory analyses in Phase II studies indicated no significant pharmacokinetic interaction between Vicadrostat and empagliflozin; neither drug appeared to affect the plasma exposure of the other.17
• Excretion: The mean elimination half-life (t1/2) of Vicadrostat is reported to be between 4.4 and 6.3 hours.[14] This relatively short half-life typically suggests that consistent daily dosing is required to maintain steady-state plasma concentrations. Specific details regarding the routes and proportions of excretion (e.g., renal vs. fecal) or extensive data on tissue distribution and protein binding are not comprehensively covered in the provided sources.

B. Observed Ethnic Variations in Pharmacokinetic Parameters

Phase 1 pharmacokinetic studies have revealed some ethnic variations. Plasma exposure to Vicadrostat was observed to be slightly higher in Asian participants (of Chinese or Japanese descent) compared to European participants.[14] This difference in exposure has been hypothesized to be related, at least in part, to lower average body weight in the Asian participants studied.[14] Recognizing and characterizing such ethnic differences is crucial for global drug development. Consequently, clinical trials have specifically included Chinese and Japanese participants to evaluate the safety and tolerability of Vicadrostat in these populations.[3] These findings underscore the importance of careful monitoring in global Phase III trials and may necessitate specific dose considerations or pre-specified subgroup analyses for these populations in the final drug labeling if the observed pharmacokinetic differences translate into clinically significant variations in efficacy or safety.

Table 2: Summary of Key Pharmacokinetic Parameters of Vicadrostat

Parameter	Value	Reference(s)
Tmax (median)	0.50–1.75 hours	14
Mean Half-life (t1/2)	4.4–6.3 hours	14
Effect of High-Fat Meal on Absorption	Reduced rate, but not extent of absorption	14
Primary Metabolic Pathways	Glucuronidation via UGT2B7 and UGT2B4	17
Noted Ethnic Differences	Slightly higher plasma exposure in Asian (Chinese/Japanese) vs. European participants (possibly body weight related)	14

V. Clinical Development and Efficacy

Vicadrostat is undergoing a robust clinical development program, primarily focusing on its potential in chronic kidney disease (CKD) and heart failure with preserved ejection fraction (HFpEF). Boehringer Ingelheim's significant investment in pursuing these dual indications through large Phase III trials highlights a strong belief in Vicadrostat's broad cardiorenal protective capabilities, leveraging the established understanding of aldosterone's detrimental role in both the kidney and the heart.

A. Investigational Use in Chronic Kidney Disease (CKD)

• Rationale: Elevated aldosterone levels are strongly correlated with adverse cardiorenal outcomes in individuals with CKD, including accelerated decline in estimated glomerular filtration rate (eGFR), increased proteinuria (albuminuria), promotion of renal inflammation, and progression of fibrosis.[14] While current standard-of-care therapies, such as renin-angiotensin system inhibitors (RASi) and sodium-glucose cotransporter-2 inhibitors (SGLT2i), provide significant benefits, a substantial residual risk often remains, and these agents may not fully counteract the detrimental effects of aldosterone.[16] Vicadrostat, by directly inhibiting aldosterone synthesis, aims to slow the progression of kidney damage and reduce cardiovascular risks in this vulnerable patient population.[1]
• Summary of Phase I and II Trial Findings:
• A Phase I trial involving 58 participants with type 2 diabetes and albuminuric CKD (eGFR 20 to <75 ml/min/1.73 m2, UACR ≥200 to <3500 mg/g) investigated Vicadrostat at doses of 3 mg, 10 mg, or 40 mg daily for 28 days. The drug was generally well tolerated, effectively suppressed plasma aldosterone levels, and showed a promising signal for reducing albuminuria. UACR responses, defined as a decrease of ≥20% from baseline, were observed in 80% of participants receiving Vicadrostat 40 mg compared to 37.5% in the placebo group.[13]
• More extensive Phase II data from a study involving 586 patients with albuminuric CKD demonstrated that Vicadrostat 10 mg daily reduced UACR by approximately 40% compared to placebo. This effect was observed whether Vicadrostat was given as monotherapy or concurrently with empagliflozin.[16] These encouraging Phase II results were presented at the American Society of Nephrology (ASN) Kidney Week in November 2023.[1]
• The combination of Vicadrostat with empagliflozin yielded particularly noteworthy results, with some analyses showing a significant reduction in albuminuria by up to 40% [21], and others indicating a potentially synergistic UACR reduction of approximately 61%.[5] Furthermore, up to 70% of participants achieved a clinically meaningful UACR reduction (≥30%) when Vicadrostat was administered on top of empagliflozin therapy.[22]
• Detailed Overview of the EASi-KIDNEY Phase III Trial (NCT06531824): The promising early-phase data paved the way for the large-scale EASi-KIDNEY (Evaluating Aldosterone Synthase inhibition in KIDNEY disease) Phase III trial.
• Design: This is a multinational, randomized, double-blind, placebo-controlled trial aiming to enroll approximately 11,000 patients.[16] Participants are randomized to receive either Vicadrostat 10 mg once daily in combination with empagliflozin 10 mg once daily, or placebo in combination with empagliflozin 10 mg once daily, in addition to standard medical care.[17] The trial incorporates an initial run-in phase where participants are started on or switched to study-provided empagliflozin before randomization.[17]
• Patient Population: The trial enrolls adults with CKD, both with and without diabetes, who are at risk of progressive kidney disease. A key feature of the trial's design is its large sample size, which is intended to provide sufficient statistical power to assess treatment effects in patients with and without diabetes as separate subgroups.[16] While specific eGFR inclusion criteria for EASi-KIDNEY are not fully detailed in the provided materials beyond targeting CKD patients, related heart failure trials exclude eGFR <20 mL/min/1.73 m2.[24]
• Primary Outcome: The primary endpoint is a composite outcome measuring kidney disease progression, hospitalization for heart failure, and cardiovascular death.[17] Earlier descriptions also mention the assessment of overall safety and cardiorenal efficacy.[16]
• Rationale/Goal: The fundamental objective is to determine if the addition of Vicadrostat to empagliflozin therapy can lead to improved cardiorenal outcomes and slow the progression of CKD more effectively than empagliflozin alone.[16]
• Status: The EASi-KIDNEY trial commenced recruitment in September 2024.[21] Full results from this pivotal study are anticipated in 2028 or 2029.[21]

B. Investigational Use in Heart Failure (HFpEF)

• Rationale: Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome characterized by symptoms and signs of heart failure despite a normal or near-normal left ventricular ejection fraction (typically LVEF ≥40% or ≥50%). The pathophysiology often involves diastolic dysfunction, where the left ventricle does not fill adequately with blood, frequently due to increased myocardial stiffness.[4] Elevated aldosterone levels are believed to contribute to this pathophysiology through mechanisms promoting inflammation, fibrosis, and vascular dysfunction.[4] There remains a significant unmet medical need for effective treatments for HFpEF that can favorably modify the disease course, particularly those that can lower aldosterone levels.[4]
• Summary of Relevant Trial Findings (prior to Phase III): While specific Phase II trial data for Vicadrostat exclusively in an HFpEF population are not detailed in the provided sources, the promising results in CKD (demonstrating UACR and blood pressure reductions with Vicadrostat plus empagliflozin) are relevant.[1] CKD and HFpEF frequently coexist and share common risk factors and pathophysiological mechanisms, including aldosterone dysregulation. The mechanistic rationale for aldosterone synthase inhibition in HFpEF is strong.
• Detailed Overview of the EASi-HF™ Phase III Trial (e.g., NCT06424288, NCT06935370): The EASi-HF™ (Evaluating Aldosterone Synthase inhibition in Heart Failure) program includes Phase III trials investigating Vicadrostat in heart failure.
• Design: NCT06424288 is a Phase III, randomized, double-blind, placebo-controlled trial designed to enroll approximately 6,000 participants.[4] Participants are randomized to receive either Vicadrostat in combination with empagliflozin or placebo in combination with empagliflozin, administered once daily, on top of standard of care.[4]
• Patient Population: This trial enrolls adults (aged 18 years or older) with chronic heart failure (diagnosed at least 3 months prior), New York Heart Association (NYHA) functional class II-IV, and a left ventricular ejection fraction (LVEF) of ≥40%.[4] Key inclusion criteria also mandate evidence of structural heart abnormality (e.g., left ventricular hypertrophy or left atrial enlargement) and elevated levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), with specific thresholds varying based on body mass index (BMI) and the presence of atrial fibrillation or flutter.[12] Exclusion criteria are comprehensive and include recent use of mineralocorticoid receptor antagonists (MRAs), treatment with certain other cardiovascular medications, recent major cardiovascular events or surgeries, and specific types of cardiomyopathy (e.g., infiltrative diseases like amyloidosis, hypertrophic obstructive cardiomyopathy).[12] The careful patient selection criteria, particularly the LVEF ≥40% threshold combined with NT-proBNP levels and evidence of structural heart disease, are designed to enroll a well-characterized HFpEF population. This is critical because HFpEF is a notoriously heterogeneous syndrome, and previous trials have often struggled due to this variability. Such precise enrollment criteria aim to enrich the study with patients who have "true" HFpEF and are most likely to benefit from aldosterone modulation, thereby increasing the probability of demonstrating a treatment effect if one exists.
• Primary Outcome: The primary purpose is to determine if Vicadrostat in combination with empagliflozin provides clinical benefits for people with HFpEF.[12] This is likely to be a composite endpoint of cardiovascular death or hospitalization due to heart failure.[25]
• Status: The NCT06424288 trial was open for recruitment as of April 2025, with a study start date of June 17, 2024, and an estimated primary completion date of November 15, 2027.[12] Another related Phase 3 trial, NCT06935370, is listed for Vicadrostat in combination with empagliflozin for heart failure, potentially targeting patients with a weak pumping function of the left side of the heart (suggesting HFrEF or borderline EF).[26]

The strategic decision to include empagliflozin as a background/combination therapy in both major Phase III programs (EASi-KIDNEY and EASi-HF) is noteworthy. This approach not only aims for synergistic efficacy but also sets a high benchmark by requiring Vicadrostat to demonstrate added benefit over an already effective SGLT2 inhibitor. This design anticipates the evolving standard of care where SGLT2 inhibitors are becoming foundational therapies for both CKD and HF, positioning Vicadrostat to complement, rather than compete with, this established class.

C. Regulatory Status Highlights

• Vicadrostat (BI 690517) received Fast Track Designation from the U.S. Food and Drug Administration (FDA) in October 2022 for the CKD indication.[1] This designation is intended to facilitate the development and expedite the review of drugs that treat serious conditions and fill an unmet medical need.
• It is crucial to note that Vicadrostat remains an investigational drug. It has not yet been approved for any proposed indication by any regulatory authority, including the U.S. FDA or the European Medicines Agency (EMA).[4] Its use is currently restricted to clinical trials.[3]

Table 3: Overview of Major Clinical Trials for Vicadrostat

Trial Identifier/Name	Phase	Target Indication	Key Intervention(s)	Primary Outcome(s) (general)	Number of Participants	Status (latest available)	Reference(s)
EASi-KIDNEY (NCT06531824)	III	Chronic Kidney Disease (CKD)	Vicadrostat (10mg) + Empagliflozin (10mg) vs. Placebo + Empagliflozin (10mg)	Composite of kidney disease progression, hospitalization for heart failure, cardiovascular death	~11,000	Recruiting	16
EASi-HF™ (e.g., NCT06424288)	III	Heart Failure with Preserved Ejection Fraction (HFpEF; LVEF ≥40%)	Vicadrostat + Empagliflozin vs. Placebo + Empagliflozin	Reduction in CV death or hospitalization for HF	~6,000	Recruiting	4

VI. Combination Therapy with Empagliflozin

A central pillar of Vicadrostat's late-stage clinical development strategy is its investigation as part of a combination therapy with empagliflozin, an established SGLT2 inhibitor. This proactive approach, evident from Phase II studies in CKD and forming the basis of the Phase III programs for both CKD and HF, aims to maximize the benefit/risk profile rather than pursuing Vicadrostat as a monotherapy first.

A. Rationale for Combining Vicadrostat with an SGLT2 Inhibitor (Empagliflozin)

The rationale for this combination is multifaceted:

• Complementary Mechanisms of Action: Vicadrostat, as an ASi, directly inhibits aldosterone production, thereby targeting aldosterone-driven inflammation, fibrosis, and sodium retention.[3] Empagliflozin, an SGLT2 inhibitor, primarily works by reducing glucose reabsorption in the kidneys, leading to glucosuria, but also exerts beneficial cardiorenal effects through mechanisms such as reducing intraglomerular pressure, natriuresis, and potentially direct cardiac and vascular effects.[5] The targeting of these distinct yet complementary pathophysiological pathways holds the potential for additive or synergistic therapeutic benefits.[5]
• Addressing Residual Cardiorenal Risk: Despite the proven efficacy of foundational therapies like RAS inhibitors and SGLT2 inhibitors, many patients with CKD and HF continue to face a significant residual risk of disease progression and adverse outcomes. Aldosterone breakthrough, where aldosterone levels escape suppression despite RAS inhibition, is a known concern.[18] The addition of an ASi like Vicadrostat aims to specifically target this residual aldosterone-mediated risk component.[16]
• Potential for Improved Tolerability, Notably Hyperkalemia Mitigation: A key and frequently cited rationale for the combination is the potential for empagliflozin to mitigate the risk of hyperkalemia (elevated serum potassium levels), a known adverse effect associated with therapies that inhibit the aldosterone pathway, including ASIs and MRAs.[4] SGLT2 inhibitors have been observed to have a neutral or even a modest potassium-lowering effect, possibly due to osmotic diuresis and other renal tubular effects.[5]
• Broad Cardiovascular-Renal-Metabolic (CRM) Benefits: Both ASIs (via aldosterone modulation) and SGLT2 inhibitors have demonstrated benefits across the spectrum of cardiovascular, renal, and metabolic conditions. The combination therapy is envisioned to improve overall CRM health, with the understanding that positive outcomes in one of these interconnected systems may translate into benefits in others.[4]

B. Evidence of Synergistic or Enhanced Effects on Efficacy Markers

Early clinical data suggest that the combination of Vicadrostat and empagliflozin may indeed lead to enhanced effects on important surrogate markers:

• UACR Reduction: As previously noted, Phase II CKD trial data indicated that the combination of Vicadrostat 10 mg and empagliflozin resulted in a UACR reduction of approximately 61%. This was greater than the approximate 40% reduction seen with Vicadrostat monotherapy and the approximate 30% reduction with empagliflozin monotherapy in similar patient populations.[5] Other reports also highlighted significant albuminuria reduction with the combination.[21]
• Blood Pressure Reduction: The combination was also reported to lower systolic blood pressure by 7.8 mmHg, a more substantial reduction than achieved by either Vicadrostat or empagliflozin alone in the studied context.[5]

These observations of enhanced efficacy on surrogate markers in Phase II studies provide a strong foundation for the ongoing large Phase III outcome trials, which will determine if these effects translate into improved hard clinical endpoints.

C. Potential for Mitigating Adverse Effects (e.g., Hyperkalemia)

Hyperkalemia is a significant concern and a dose-limiting toxicity for many drugs that interfere with the RAAS, including ASIs and MRAs.[5] The co-administration of an SGLT2 inhibitor like empagliflozin is hypothesized to counteract or attenuate this risk.[4] If effective, this could improve the overall tolerability of Vicadrostat therapy, potentially allowing a wider range of patients to be treated, including those with higher baseline serum potassium levels or those more susceptible to hyperkalemia.[16]

However, it is important to note that while empagliflozin may mitigate this risk, Phase II data still showed a mean increase in serum potassium of +0.24 to +0.32 mmol/L with the Vicadrostat and empagliflozin combination.[5] This increase is comparable to, or slightly higher than, that reported for the non-steroidal MRA finerenone (approximately +0.21 mmol/L).[5] This indicates that hyperkalemia remains a tangible risk with the combination therapy and necessitates diligent monitoring and management strategies, such as dietary potassium restriction and regular serum potassium checks, as outlined in patient information for the Phase III trials.[20] The ultimate success of this hyperkalemia mitigation strategy will be a critical aspect evaluated in the large Phase III trials, determining if the risk is sufficiently managed to allow broad clinical application across diverse patient populations.

The deliberate positioning of Vicadrostat as an "add-on" therapy to an SGLT2 inhibitor could streamline its adoption if approved, as clinicians are already familiar with empagliflozin and its class. However, this strategy also intrinsically links Vicadrostat's utility to the continued prominence and perception of SGLT2 inhibitors as a standard of care, and raises questions about its use with other SGLT2 inhibitors or in patients unable to tolerate them, which current trials are not primarily designed to answer.

VII. Safety, Tolerability, and Risk Management

The safety and tolerability profile of Vicadrostat is being extensively evaluated in ongoing clinical trials. Data from early-phase studies provide initial insights into its adverse event profile and potential risks.

A. Adverse Event Profile

General Tolerability (Phase 1 in Healthy Volunteers):

Four Phase 1 studies conducted in healthy European, Chinese, and Japanese male volunteers indicated that single and multiple oral doses of Vicadrostat up to 80 mg were generally well tolerated.14 The proportion of participants reporting drug-related adverse events (AEs) varied across these studies: 8.3% in the European single rising dose (SRD) study, 21.4% in the Chinese/Japanese SRD study, 13.9% in the European multiple rising dose (MRD) study, and 2.8% in the Japanese MRD study.14 Notably, no serious AEs, deaths, or AEs leading to treatment discontinuation were reported in these healthy volunteer studies, with the exception of one reported AE of severe orthostatic hypotension in the European SRD study.14

General Tolerability (Phase 1 in CKD Patients):

In a Phase I trial that enrolled 58 participants with type 2 diabetes and albuminuric CKD, Vicadrostat (at doses of 3 mg, 10 mg, or 40 mg daily for 28 days) was also found to be generally well tolerated. Drug-related AEs were experienced by 13.8% of participants receiving Vicadrostat, with most AEs being mild to moderate in severity.13

Commonly Reported Adverse Events and Key Safety Considerations:

Based on available data, the following AEs and safety considerations are prominent:

• Hyperkalemia: This is consistently identified as the main and most significant dose-related side effect of Vicadrostat, a predictable consequence of aldosterone synthesis inhibition leading to reduced potassium excretion.[5]
• Incidence and Magnitude: Aldosterone synthase inhibitors as a class have demonstrated a risk ratio (RR) of 2.5 for hyperkalemia compared to placebo (P<0.02) in hypertensive patients, with hyperkalemia occurring in 6.2% of ASI-treated patients versus 1.2% in the placebo group.[23] In the Phase I CKD trial with Vicadrostat, hyperkalemia was reported in 1 out of 18 participants in the 3 mg group and 1 out of 13 in the 10 mg group; one instance of severe hyperkalemia (serum potassium 6.9 mmol/L) occurred in a participant receiving 10 mg of Vicadrostat.[13] The combination of Vicadrostat with empagliflozin was associated with a mean serum potassium increase of +0.24 to +0.32 mmol/L in Phase II.[5]
• Management: Due to this risk, serum potassium levels are closely monitored at every study visit in ongoing trials.[17] Management strategies include dietary modification (e.g., adherence to a low potassium diet), and potentially adjustment of concomitant medications or initiation of potassium-lowering agents if required.[20] The co-administration with empagliflozin is partly intended to mitigate this risk. The manageability of hyperkalemia is a critical determinant of Vicadrostat's overall benefit-risk profile.
• Hypotension/Orthostatic Hypotension: Given Vicadrostat's blood pressure-lowering effects, hypotension is a potential AE. One case of severe orthostatic hypotension was noted in Phase 1 healthy volunteer studies.[14] Blood pressure is routinely monitored during clinical trials, and adjustments to other antihypertensive medications may be necessary.[20]
• Potential Cortisol Effects: Due to the proximity of aldosterone synthase (CYP11B2) and cortisol synthase (CYP11B1) in the steroidogenic pathway, there is a theoretical risk of affecting cortisol production. However, Vicadrostat's high selectivity for CYP11B2 is designed to minimize this. Blood cortisol levels are monitored in clinical trials.[20] Symptoms of low cortisol (fatigue, nausea, hypotension, hypoglycemia) or high cortisol (easy bruising, facial redness, stretch marks) are watched for.[20] Reassuringly, Phase II data suggested no significant change in cortisol levels with Vicadrostat [5], and no symptomatic episodes of low serum cortisol were reported in approximately 700 CKD patients in Phase II studies.[17]
• Constipation: This was reported infrequently in the Phase I CKD trial (one participant in the 10 mg group and one in the 40 mg group).[13]
• Dehydration and Acute Kidney Injury (AKI): A risk of dehydration, potentially leading to a temporary fall in kidney function (AKI), is mentioned as a precaution, particularly if fluid intake is inadequate or during intercurrent illness.[20]
• Temporary Kidney Function Decrease: A slight decrease in eGFR may be observed upon initiating treatment with Vicadrostat (and empagliflozin). This may not necessarily be detrimental and could, in some cases, reflect hemodynamic changes associated with renal protection (similar to effects seen with ACE inhibitors or SGLT2 inhibitors) or simply natural fluctuations in kidney function.[17]

Serious Adverse Events (SAEs):

The incidence of SAEs specifically attributed to Vicadrostat in early trials appears low. A meta-analysis of ASIs (as a class) for hypertension found a non-significant risk ratio of 1.0 for serious adverse events compared with placebo, and no treatment-related deaths were reported.23

The relatively low rates of other serious adverse events and the good general tolerability observed in early phases—apart from the primary concern of hyperkalemia and occasional hypotension—suggest a potentially favorable overall safety profile. This is particularly true if hyperkalemia can be effectively managed through strategies like co-administration with empagliflozin, careful patient selection, and diligent monitoring. Vicadrostat's high selectivity against cortisol synthase appears to be a key factor in avoiding adrenal steroidogenesis-related issues that plagued older, less selective ASIs.

Table 4: Reported Adverse Events and Safety Considerations with Vicadrostat from Clinical Trials

Adverse Event/Consideration	Incidence/Frequency Notes	Severity Notes	Key Management Considerations	Reference(s)
Hyperkalemia	Most common/significant; Predictable effect. RR 2.5 for ASIs vs placebo (class data). Serum K+ change +0.24–0.32 mmol/L (with empagliflozin in PhII).	Can be severe (e.g., one case of 6.9 mmol/L in PhI CKD).	Close monitoring of serum K+, dietary potassium restriction, potential medication adjustments, possible mitigation by SGLT2i.	5
Hypotension/Orthostatic Hypotension	One severe case in Ph1 healthy volunteers; BP lowering is an expected pharmacodynamic effect.	Can be severe.	Blood pressure monitoring, potential adjustment of concomitant antihypertensive medications.	14
Cortisol Level Alterations	Monitored in trials; no symptomatic low cortisol in ~700 PhII CKD patients; no significant change in cortisol reported from PhII.	Potential for symptoms if levels are significantly altered.	Monitoring of cortisol levels at specific trial timepoints as per protocol.	5
Constipation	Reported infrequently in Ph1 CKD trial (low numbers).	Generally mild to moderate.	Symptomatic treatment if required.	13
Dehydration/Acute Kidney Injury	Precaution mentioned in patient information.	Can be serious if it occurs.	Ensure adequate fluid intake, especially during hot weather or illness.	20
Kidney Function Decrease (initial)	May be observed on starting treatment.	Usually mild and may be transient or reflect hemodynamic changes.	Monitoring of renal function; may not always indicate harm.	17

B. Drug Interactions

• UGT Enzyme Modulators: Since Vicadrostat is metabolized by UGT2B7 and UGT2B4, there is a potential for drug interactions with compounds that modulate these enzymes.[17]
• UGT Inhibitors: Concomitant administration of strong inhibitors of UGTs (e.g., probenecid, valproic acid, fluconazole, amitriptyline, clomipramine) should be approached with caution, as they could increase Vicadrostat plasma concentrations and potentially enhance its effects or adverse reactions.[17]
• UGT Inducers: Conversely, potent UGT inducers (e.g., rifampin, phenytoin) could theoretically decrease Vicadrostat concentrations, potentially reducing its efficacy.[17] While UGT-mediated interactions might be less frequently encountered or studied than CYP450-mediated ones, they still warrant clinician awareness. This is particularly relevant as patients with CKD and HF often have polypharmacy, and some common drugs (like valproic acid or certain systemic antifungals such as fluconazole) could interact. This highlights the need for comprehensive drug interaction screening by prescribers and potentially further dedicated interaction studies.
• Empagliflozin: As mentioned earlier, exploratory analyses in Phase II studies did not reveal any clinically significant pharmacokinetic interactions between Vicadrostat and empagliflozin; neither drug appeared to substantially affect the exposure levels of the other.[17]
• RAAS Inhibitors (ACEi, ARBs, MRAs): While not detailed as specific pharmacokinetic interactions, the co-administration of Vicadrostat with other RAAS inhibitors would be expected to increase the risk of hyperkalemia due to additive pharmacodynamic effects on potassium homeostasis. Clinical trial protocols often have specific restrictions on concomitant MRA use.[12]

C. Use in Specific Populations

• Elderly Patients: Clinical trials for heart failure (e.g., NCT06424288) include adult participants aged 18 years and older, which implicitly includes elderly individuals.[12] A meta-analysis of ASIs for hypertension included patients with a mean age of 60 years.[23] However, specific geriatric subgroup analyses or dedicated studies in the elderly for Vicadrostat are not detailed in the provided sources.
• Renal Impairment: Vicadrostat is being specifically developed for patients with CKD.[1]
• The Phase I CKD trial enrolled patients with eGFR ranging from 20 to <75 mL/min/1.73 m2.[13]
• The EASi-HF trial protocol excludes patients with an eGFR <20 mL/min/1.73 m2 or those on renal replacement therapy.[24] The precise eGFR inclusion/exclusion criteria for the EASi-KIDNEY trial are focused on a CKD population but not as explicitly detailed in the snippets.
• Hepatic Impairment: Some studies are reportedly designed to assess the tolerability of Vicadrostat in patients with liver problems.[3] However, detailed data from such studies are not available in the provided materials.

D. Contraindications and Precautions (derived from trial information)

The following contraindications and precautions are largely based on information from ongoing clinical trial protocols and patient information leaflets:

• Pregnancy and Breastfeeding: Vicadrostat is contraindicated during pregnancy and breastfeeding due to potential risks to the fetus or infant. Women of childbearing potential participating in trials must use highly effective methods of contraception throughout the study and for a specified period after its conclusion.[12]
• Hyperkalemia: This is a primary precaution. Regular monitoring of serum potassium is mandated, along with dietary counseling and potential medication adjustments.[20]
• Hypotension: Blood pressure should be monitored, as Vicadrostat can lower it.[20]
• Cortisol Levels: Monitoring of cortisol levels is part of trial protocols.[20]
• Dehydration/Acute Kidney Injury: Patients are advised to maintain adequate fluid intake, especially during periods of increased risk.[20]
• Allergic Reactions: As with any medication, allergic reactions are possible.[20]
• Specific Exclusions in HF Trials: These often include recent (within 14 days prior to screening) use of MRAs, current use of direct renin inhibitors, concurrent use of more than one ACEI, ARB, or ARNI, recent major cardiovascular events or surgeries (e.g., MI, stroke, CABG within 90 days), specific cardiomyopathies (e.g., amyloidosis, hemochromatosis, hypertrophic obstructive cardiomyopathy), acute myocarditis, and hemodynamically significant severe valvular heart disease.[12]

VIII. Regulatory Status and Future Perspectives

A. Current Regulatory Designations

Vicadrostat (BI 690517) was granted Fast Track Designation by the U.S. Food and Drug Administration (FDA) in October 2022 for the treatment of chronic kidney disease (CKD).[1] This designation is significant as it is intended to facilitate the development and expedite the review of drugs that aim to treat serious conditions and demonstrate the potential to address unmet medical needs. This suggests that regulatory authorities recognize Vicadrostat's potential to offer an improvement over existing standards of care for CKD.

B. Approval Status

It is important to emphasize that Vicadrostat is currently an investigational drug. It has not received marketing approval from any regulatory agency worldwide, including the U.S. FDA or the European Medicines Agency (EMA), for any therapeutic indication.[4] Its use is strictly limited to the context of clinical trials.[3]

C. Anticipated Timelines

The timelines for potential regulatory submission and approval are contingent upon the successful completion of ongoing Phase III trials and positive demonstration of efficacy and safety.

• The EASi-HF™ trial (NCT06424288) for heart failure has an estimated primary completion date of November 15, 2027.[24]
• Full results from the EASi-KIDNEY trial for chronic kidney disease are anticipated around 2028 or 2029.[21] Following the availability and analysis of these pivotal trial data, regulatory submissions would be prepared if the results are favorable. The subsequent review process by regulatory agencies typically takes a year or more.

D. Unmet Needs Vicadrostat Aims to Address

The development of Vicadrostat is driven by the significant unmet medical needs in its target indications:

• Chronic Kidney Disease (CKD): Despite advancements with RAS inhibitors and SGLT2 inhibitors, many patients with CKD continue to experience progressive loss of kidney function, are at high risk for developing heart failure, and face increased cardiovascular mortality.[16] Vicadrostat aims to provide an additional layer of cardiorenal protection by specifically targeting aldosterone-mediated kidney damage and cardiovascular complications.[1]
• Heart Failure with Preserved Ejection Fraction (HFpEF): HFpEF represents a major challenge in cardiovascular medicine, with limited effective treatment options compared to heart failure with reduced ejection fraction (HFrEF). There are currently no approved therapies for HFpEF that specifically and effectively lower aldosterone levels to improve clinical outcomes.[4] Vicadrostat holds the potential to fill this critical therapeutic gap.

The projected trial completion dates in the late 2020s (2027-2029) imply that Vicadrostat, if successful, will enter a therapeutic market that may have further evolved. Other novel therapies for CKD and HFpEF are also in development and could emerge by then.[1] Consequently, Vicadrostat's ultimate positioning and clinical value will depend not only on its own demonstrated efficacy and safety profile but also on how it compares to or complements other new therapeutic agents that may be available at the time of its potential launch. This underscores the dynamic and competitive nature of pharmaceutical research and development.

IX. Comparative Overview

Vicadrostat's potential role in therapy will be defined by its performance relative to existing and emerging treatments, particularly those that also modulate the RAAS or offer cardiorenal protection.

A. Positioning Relative to Mineralocorticoid Receptor Antagonists (MRAs)

MRAs, such as the non-steroidal finerenone and the older steroidal agents spironolactone and eplerenone, are established therapies that block the effects of aldosterone at the mineralocorticoid receptor.

• Mechanism: Vicadrostat inhibits aldosterone synthesis at the level of the CYP11B2 enzyme [5], representing a more upstream point of intervention compared to MRAs, which block the mineralocorticoid receptor.[5]
• Efficacy (UACR Reduction): In Phase II CKD trials, Vicadrostat (10 mg) as monotherapy showed an approximate 40% UACR reduction, and in combination with empagliflozin, this increased to around 61%.[5] Finerenone, in its pivotal FIDELIO-DKD and FIGARO-DKD trials, demonstrated UACR reductions in the range of 30–40%.[5]
• Serum Potassium Change: Both ASIs and MRAs carry a risk of hyperkalemia. Vicadrostat (in combination with empagliflozin) was associated with a mean serum potassium increase of +0.24 to +0.32 mmol/L in Phase II, while finerenone showed an increase of approximately +0.21 mmol/L.[5]
• Cortisol Impact and Hormonal Side Effects: A key differentiator for Vicadrostat is its high selectivity for aldosterone synthase over cortisol synthase, resulting in no significant reported changes in cortisol levels.[5] Steroidal MRAs like spironolactone are known for off-target hormonal side effects (e.g., gynecomastia, menstrual disturbances) due to interactions with androgen and progesterone receptors. Non-steroidal MRAs like finerenone have a much lower propensity for these steroidal side effects. Vicadrostat, being non-steroidal and acting on synthesis rather than receptor blockade, is also expected to avoid these issues.
• Trial Design Context: Vicadrostat is primarily being evaluated as an add-on to SGLT2 inhibitor therapy in large outcome trials [5], whereas MRAs like finerenone have been extensively studied in combination with RAS inhibitors.[5]

The critical comparison with finerenone will be closely watched. Both agents target the detrimental effects of aldosterone but through distinct mechanisms. Clinicians will ultimately weigh their respective efficacy on hard outcomes, UACR and blood pressure effects, the magnitude and manageability of hyperkalemia risk, overall side effect profiles (with Vicadrostat's selectivity for cortisol synthesis being a potential advantage), and patient population-specific benefits. The nuanced differences in Phase II data regarding UACR reduction and potassium elevation suggest that there might be specific patient profiles better suited for one approach over the other, or potentially for combination if safety allows, though this is speculative.

B. Positioning Relative to SGLT2 Inhibitors (e.g., Empagliflozin) as Monotherapy

SGLT2 inhibitors have become a cornerstone in the management of CKD and various types of heart failure.

• Mechanism: Vicadrostat's primary effect is through reducing aldosterone production, thereby targeting aldosterone-driven inflammation and fibrosis.[5] Empagliflozin and other SGLT2 inhibitors exert their cardiorenal benefits through multiple mechanisms, including reduced glucose reabsorption, natriuresis, improved glomerular hemodynamics, and potentially direct vascular and cardiac effects, which are distinct from aldosterone synthesis inhibition.[5]
• Efficacy (UACR Reduction): Empagliflozin monotherapy has been shown to reduce UACR by approximately 30% in CKD patients. Vicadrostat monotherapy achieved about a 40% reduction in similar settings. The combination of Vicadrostat and empagliflozin demonstrated a UACR reduction of around 61%.[5]
• Blood Pressure: The combination of Vicadrostat and empagliflozin produced a greater systolic blood pressure reduction (-7.8 mmHg) than was reported for either agent alone in the comparative context.[5]
• Clinical Utility: The development strategy for Vicadrostat clearly positions it as an add-on therapy to SGLT2 inhibitors, aiming to provide incremental benefits beyond what SGLT2 inhibitors achieve alone. It is not being developed as a direct competitor to SGLT2 inhibitors for use as monotherapy in their established indications. This pragmatic approach recognizes the foundational role of SGLT2 inhibitors and seeks to build upon it by targeting a complementary pathophysiological pathway.

C. Other Pipeline Therapies for CKD

The therapeutic pipeline for CKD is active, with several other promising agents in advanced stages of development. These include ziltivekimab (an anti-interleukin-6 [IL-6] monoclonal antibody), zibotentan in combination with dapagliflozin (an endothelin receptor antagonist combined with an SGLT2 inhibitor), and lorundrostat (another aldosterone synthase inhibitor).[1] Vicadrostat is thus entering a competitive and innovative field. Its ultimate success and market penetration will depend on its comparative efficacy, safety profile, ease of use, and its ability to carve out a distinct therapeutic niche relative to these other emerging therapies.

Table 5: Comparative Profile: Vicadrostat vs. Select Aldosterone-Modulating Agents and SGLT2i

Parameter	Vicadrostat (+ Empagliflozin)	Non-steroidal MRAs (e.g., Finerenone)	Empagliflozin (monotherapy)	Reference(s)
Mechanism of Action	Aldosterone synthase inhibition (+ SGLT2 inhibition)	Mineralocorticoid receptor blockade	SGLT2 inhibition	5
UACR Reduction (approx. from PhII/III)	~61% (combo); ~40% (Vicadrostat alone)	~30-40%	~30%	5
Systolic BP Effect (approx.)	-7.8 mmHg (combo)	Significant reduction (ASIs class: -6.3 mmHg)	Moderate reduction	5
Hyperkalemia Risk	Increased (e.g., mean K+ change +0.24–0.32 mmol/L with combo)	Increased (e.g., mean K+ change +0.21 mmol/L)	Neutral or potential to decrease risk when combined with K+-increasing drugs	5
Cortisol Impact	No significant change (due to high selectivity for CYP11B2)	No direct impact on cortisol synthesis (non-steroidal)	No direct impact	5

X. Conclusion

Vicadrostat (BI 690517) emerges from current research as a novel, potent, and highly selective aldosterone synthase inhibitor, holding considerable promise for the treatment of chronic kidney disease and heart failure with preserved ejection fraction. Developed by Boehringer Ingelheim, its core mechanism involves the direct inhibition of aldosterone production, thereby targeting a key driver of cardiorenal pathophysiology. This approach has demonstrated encouraging pharmacodynamic effects in early clinical trials, including significant reductions in plasma aldosterone levels, urine albumin-to-creatinine ratio, and blood pressure.

A defining feature of Vicadrostat's development is its strategic investigation primarily in combination with the SGLT2 inhibitor empagliflozin. This combination aims to leverage complementary mechanisms of action for enhanced efficacy and, crucially, to potentially mitigate the inherent risk of hyperkalemia associated with aldosterone pathway inhibition. While Phase II results support the potential for augmented benefits on surrogate markers like UACR, hyperkalemia remains a key safety consideration requiring diligent monitoring and management, even with concomitant SGLT2 inhibitor use. The high selectivity of Vicadrostat for aldosterone synthase over cortisol synthase is a significant advantage, appearing to minimize the risk of cortisol-related adverse effects that have hampered the development of previous, less selective ASIs.

The ongoing large-scale Phase III clinical trials, EASi-KIDNEY and EASi-HF™, are pivotal. Their outcomes will be critical in definitively establishing the clinical benefit-risk profile of Vicadrostat (in combination with empagliflozin) on hard cardiorenal endpoints in broad patient populations with CKD and HFpEF, respectively. These conditions continue to represent areas of substantial unmet medical need, and a positive outcome for Vicadrostat could offer a valuable new therapeutic option.

Vicadrostat represents a sophisticated advancement in targeting the renin-angiotensin-aldosterone system, moving beyond receptor blockade to highly selective synthesis inhibition. Its co-development with an SGLT2 inhibitor reflects a contemporary, multi-faceted strategy for addressing complex cardiorenal diseases. The ultimate success of Vicadrostat will depend on the strength of the forthcoming Phase III data, particularly its ability to demonstrate a compelling net clinical benefit where improved outcomes are balanced against the manageable risk of hyperkalemia, thereby solidifying its place in the future therapeutic armamentarium for these challenging conditions. Until such data are available and regulatory approvals are obtained, Vicadrostat remains an investigational agent.

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