The investigational non-steroidal MRA balcinrenone in cardiorenal medicine: current evidence and future perspectives

ABSTRACT

For almost two decades, renin–angiotensin–system (RAS) blockade was the basic pillar of therapy for cardiorenal protection in patients with chronic kidney disease (CKD) and albuminuria. Novel therapies, such as sodium-glucose co-transporter type 2 inhibitors (SGLT2is) and the non-steroidal mineralocorticoid receptor antagonist (MRA) finerenone, have been added to our therapeutic armamentarium in the last few years. Despite this substantial progress, there is still an unmet need for the development of additional therapies to mitigate the substantial residual risk of CKD patients. Balcinrenone is a novel, non-steroidal MRA that is currently under investigation for potential cardiorenal protective effects. In preclinical studies, balcinrenone was similarly effective with eplerenone in improving albuminuria and in reversing renal histopathology. Animal studies have shown a beneficial effect of balcinrenone on urinary sodium/potassium ratio that contrasts with the typical increase seen with traditional steroidal MRAs. The MIRO-CKD was a phase 2b trial showing that among 324 patients with albuminuric CKD, combination therapy with dapagliflozin and balcinrenone was safe and more effective than monotherapy with dapagliflozin in improving albuminuria over 3 months of follow-up. A large phase 3 clinical program is ongoing to investigate the long-term safety and efficacy of balcinrenone in a broad spectrum of patients with symptomatic heart failure and moderate-to-advanced CKD. In this article, we explore the tolerability, safety, and efficacy of the investigational non-steroidal MRA balcinrenone. We critically evaluate the design and key findings of the MIRO-CKD trial and provide directions for future research in this important area.

THE ROADMAP FOR THE DEVELOPMENT OF NOVEL CARDIORENAL PROTECTIVE THERAPIES IN CHRONIC KIDNEY DISEASE

For nearly two decades, agents blocking the renin–angiotensin–system (RAS) were the basic pillar of therapy to retard the progression of kidney injury and reduce the risk of heart failure (HF) hospitalization in patients with albuminuric chronic kidney disease (CKD) [1, 2]. A major breakthrough came with the recognition that the primary benefit of sodium-glucose co-transporter type 2 inhibitors (SGLT2is) extends beyond glycemic control, conferring a remarkable reduction in the risk of adverse cardiovascular and kidney events in patients with or without type 2 diabetes (T2D) [3]. Three landmark trials conducted specifically in patients with CKD were prematurely terminated due to the demonstrated efficacy of SGLT2is relative to placebo (Fig. 1) [4–6]. On this basis, SGLT2is have emerged as the second pillar of therapy and are strongly recommended in international guidelines [7, 8].

Figure 1:

Landmark randomized controlled trials demonstrating the safety and efficacy of SGLT2is and the non-steroidal MRA finerenone in patients with CKD. Abbreviations: CI = confidence interval; CREFENCE = Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation; DAPA-CKD = Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease; EMPA-KIDNEY = Study of Heart and Kidney Protection with Empagliflozin; FIDELIO-DKD = Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease; FIND-CKD = Finerenone Non-Diabetic Chronic Kidney Disease; FIGARO-DKD = Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease; HR = hazard ratio.

In a post hoc analysis of the CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial, relative to placebo, canagliflozin provoked an average 31% reduction in the levels of urinary albumin-to-creatinine ratio (UACR) at week 26 and increased the likelihood of achieving a 30% reduction in UACR [odds ratio (OR): 2.69; 95% confidence interval (CI): 2.35 to 3.07)] [9]. The levels of residual albuminuria at week 26 were found to be a strong and independent predictor of adverse cardiorenal events in overall trial population as well as in each separate treatment arm [9]. Therefore, there is a critical unmet need for additional therapies with proven safety and efficacy in further improving the cardiorenal outcomes of patients with CKD and residual albuminuria [10].

The overactivity of the mineralocorticoid receptor (MR) is another mechanism that is involved in the progression of end-organ damage in clinical conditions of relative aldosterone excess, such as in patients with cardio-kidney-metabolic diseases [11]. In a large phase 3 clinical trial program including a total of 13 026 patients with T2D and a wide spectrum of CKD who were already treated with maximum-labeled or maximally tolerated doses of a RAS blocker, the non-steroidal MR antagonist (MRA) finerenone was superior to placebo in slowing the progression of CKD and improving cardiovascular outcomes [12–14]. Finerenone appeared to offer a more favorable side effect profile than the traditional steroidal MRAs, such as spironolactone or eplerenone. In these landmark trials, severe hyperkalemic events leading to permanent discontinuation of the trial regimen occurred in a very small proportion of patients [12–14]. Accordingly, the non-steroidal MRA finerenone has received approval by regulatory agencies and is now the third guideline-directed therapy for cardiorenal protection in T2D patients with albuminuric CKD [7, 8, 15]. The recently published phase 3 FIND-CKD (Finerenone Non-Diabetic Chronic Kidney Disease) trial extended the evidence for finerenone in patients with non-diabetic CKD, showing that finerenone was safe and more effective than placebo in slowing the annual rate of eGFR (estimated glomerular filtration rate) decline over a follow-up of 32 months [16, 17]. Cardioprotective benefits of finerenone were also demonstrated in patients with HF and mildly reduced or preserved ejection fraction [18].

SGLT2is and the non-steroidal MRA finerenone have complementary mechanisms of action, generating the hypothesis that combination therapy could result in greater cardiorenal protection than the benefits provided by either therapy alone [3]. This hypothesis is supported by indirect evidence from post hoc analyses of landmark trials showing that background therapy with an SGLT2i did not significantly modify the safety profile and efficacy of finerenone versus placebo in lowering the risk of cardiorenal outcomes [19]. Conversely, subgroup analyses showed that the safety and efficacy of the SGLT2i dapagliflozin versus placebo was similar in magnitude irrespective of background treatment with a steroidal MRA [20]. More direct evidence supportive of a synergistic effect with combination therapy was provided by a phase 2 trial showing that in patients with albuminuric CKD and T2D, simultaneous initiation of the SGLT2i empagliflozin and the nonsteroidal MRA finerenone was superior to either monotherapy in lowering albuminuria [21].

Other non-steroidal MRAs are currently in different phases of clinical development, offering hope for the implementation of additional cardiorenal protective therapies in daily clinical practice. In this article, we explore the tolerability, safety, and efficacy of the investigational non-steroidal MRA balcinrenone administered in combination with the SGLT2i dapagliflozin in patients with stage 3–4 CKD and albuminuria. We critically evaluate the design and the main results of the recently published MIRO-CKD [22, 23] (Efficacy, Safety and Tolerability of Balcinrenone/Dapagliflozin Compared to Dapagliflozin in Adults with Chronic Kidney Disease) trial and we conclude with perspectives for future research in this important scientific field.

THE NON-STEROIDAL MRA BALCINRENONE: MECHANISM OF ACTION AND PRELIMINARY PRECLINICAL AND CLINICAL DATA

Unlike spironolactone and eplerenone, balcinrenone has a non-steroidal structure that allows this agent to bind in a unique manner to the MR and induce a co-factor recruitment pattern that differs from the response observed with traditional steroidal MRAs [24]. The affinity and selectivity of balcinrenone to the MR is at least similar with that of eplerenone [24]. In contrast to spironolactone, which is a prodrug with active metabolites that accumulate over time and result in a prolonged duration of action [25], balcinrenone has a short plasma half-life (2–3 h after a single dosing and 4–9 h after 8-day administration) [26–28]. In animal models of CKD, balcinrenone was similarly effective with eplerenone in reducing albuminuria, and in mitigating the histopathological lesions of extracellular matrix deposition, mainly through anti-inflammatory and anti-fibrotic mechanisms of action [29]. Other experimental studies showed that balcinrenone and eplerenone prevented in a similar manner the progression of cardiac damage in an animal model of streptozotocin-induced diabetic mice [30]. Notably, preclinical studies suggested a preferentially higher urinary potassium excretion with the MR modulator balcinrenone than with eplerenone [31]. The distinct mechanism of action of balcinrenone together with its unique pharmacokinetic properties and its favorable effect on urinary potassium handling may result in a lower risk of treatment-induced hyperkalemia and/or more rapid correction of hyperkalemia after transient treatment discontinuation.

Preliminary clinical data for the tolerability, safety, and efficacy of balcinrenone were provided by the MIRACLE (Efficacy, Safety and Tolerability of AZD9977 and Dapagliflozin in Participants with Heart Failure and Chronic Kidney Disease) [32], a phase 2b trial enrolling patients with symptomatic HF, left ventricular ejection fraction <60%, eGFR 30–60 ml/min/1.73 m², and UACR ≥30 to <3000 mg/g. In this dose-ranging trial, 133 patients were randomized to receive double-blind therapy with balcinrenone 15, 50, or 150 mg/day plus dapagliflozin 10 mg/day or the combination of dapagliflozin 10 mg/day with placebo [32]. Over a follow-up period of 12 weeks, there was no statistically significant difference in the change of UACR from baseline to week 12 between the balcinrenone plus dapagliflozin and the dapagliflozin plus placebo groups [32]. There was a trend toward a dose-dependent reduction in plasma biomarkers of cardiac injury and dose-dependent elevations in plasma potassium levels. Permanent discontinuation of therapy due to hyperkalemia occurred in two patients in the balcinrenone plus dapagliflozin groups and in zero patients treated with dapagliflozin plus placebo [32]. However, it has to be noted that the MIRACLE trial was prematurely terminated due to a low recruitment rate, possibly influenced by the trial being largely undertaken during the COVID-19 pandemic and that patients with albuminuria were being recruited from cardiology clinics. Therefore, MIRACLE was not adequately powered to provide direct and definitive evidence for the benefit–risk profile of balcinrenone in patients with symptomatic HF and CKD.

THE DESIGN AND KEY FINDINGS OF THE MIRO-CKD TRIAL

Similarly with MIRACLE [32], MIRO-CKD was a dose-finding, phase 2b trial (Table 1) [22, 23]. Patients were eligible for enrollment, if they had an eGFR of 25 to <60 ml/min/1.73 m², a UACR of >100 to ≤5000 mg/g, and a serum potassium concentration of 3.5–5.0 mmol/l. In total, 324 patients fulfilling the prespecified selection criteria were randomly assigned in a 1:1:1 ratio to receive combination therapy with balcinrenone 40 mg/day and dapagliflozin 10 mg/day, balcinrenone 15 mg/day and dapagliflozin 10 mg/day, or dapagliflozin 10 mg/day and placebo [22]. MIRO-CKD truly enrolled a globally representative population of patients with albuminuric CKD at high risk for disease progression. At baseline, the mean levels of eGFR were 42.2 ± 10.5 ml/min/1.73 m² and the median levels of UACR were 365 mg/g. Before randomization, 86.4% of patients (n = 280) were receiving a RAS blocker, whereas 56.2% of patients (n = 182) were already being treated with an SGLT2i [22]. These baseline data indicate that MIRO-CKD enrolled a CKD population receiving optimized guideline-directed background therapy.

Table 1:

The design and key findings of the MIRO-CKD trial.

Parameter	MIRO-CKD trial [23]
Year	2025
Patient characteristics	Patients with eGFR of 25 to <60 ml/min/1.73 m2, UACR of >100 to ≤5000 mg/g and a serum potassium concentration of 3.5–5.0 mmol/l
N	324
Intervention	Balcinrenone 40 mg/day plus dapagliflozin 10 mg/day or balcinrenone 15 mg/day plus dapagliflozin 10 mg/day vs. dapagliflozin 10 mg/day plus placebo on top of standard of care
Follow-up (weeks)	12
eGFR at baseline (ml/min/1.73 m2)	42.2 ± 10.5 (mean)
UACR at baseline (mg/g)	365 (median)
RAS blocker use at baseline (n, %)	280 (86.4%)
SGLT2i use before randomization (n, %)	182 (56.2%)
Primary efficacy outcome	Between-group differences in the change from baseline of UACR
Between-group differences in UACR	At week 12, relative to dapagliflozin 10 mg/day plus placebo, the difference in UACR was −22.8% (95% CI: −33.3% to −10.7%) in the balcinrenone 15 mg/day plus dapagliflozin 10 mg/day group and −32.8% (95% CI: −42.0% to −22.1%) in the balcinrenone 40 mg/day plus dapagliflozin 10 mg/day group
Safety endpoints	The incidence of any serum potassium elevation >5.5 mmol/l, analyzed at central or local laboratory, was 13% in the balcinrenone 40 mg/day plus dapagliflozin 10 mg/day group, 7% in the balcinrenone 15 mg/day plus dapagliflozin 10 mg/day group, and 5% of the dapagliflozin 10 mg/day plus placebo group

Abbreviations: CI = confidence interval; eGFR = estimated glomerular filtration rate; MIRO-CKD = Efficacy, Safety and Tolerability of Balcinrenone/Dapagliflozin Compared to Dapagliflozin in Adults with Chronic Kidney Disease; RAS = renin–angiotensin–system; SGLT2i = sodium-glucose co-transporter type 2 inhibitor; UACR = urinary albumin-to-creatinine ratio.

Over 12 weeks of follow-up, as compared with the dapagliflozin plus placebo group, the proportional reduction from baseline to week 12 in the levels of UACR was 32.8% greater for the combination of balcinrenone 40 mg/day plus dapagliflozin 10 mg/day (between-group difference: −32.8%; 95% CI: −42.0% to –22.1%) and 22.8% greater for the combination of balcinrenone 15 mg/day plus dapagliflozin 10 mg/day (between-group difference: −22.8%; 95% CI: −33.3% to −10.7%) [23]. Similarly, a ≥30% reduction in UACR from baseline to week 12 was achieved more frequently in the balcinrenone 40 mg/day plus dapagliflozin 10 mg/day group (47.3%) and the balcinrenone 15 mg/day plus dapagliflozin 10 mg/day group (36.1%) than in the dapagliflozin 10 mg/day plus placebo group (30.2%) [23]. The greater albuminuria-lowering effect of the combination of balcinrenone with dapagliflozin was irrespective of the diabetic status of patients and treatment with a RAS blocker or an SGLT2i prior to study enrollment [23].

With respect to the safety of the intervention, hyperkalemic events, defined as any local or central laboratory potassium elevation >5.5 mmol/l, occurred numerically more commonly in the balcinrenone 40 mg/day plus dapagliflozin 10 mg/day group (13.0%) and in the balcinrenone 15 mg/day plus dapagliflozin 10 mg/day group (7.0%) as compared with the dapagliflozin 10 mg/day plus placebo group (5.0%) [23]. Severe hyperkalemia leading to study drug discontinuation occurred rarely over the 3-month follow-up period of the MIRO-CKD trial (only three cases). However, the accumulated risk of hyperkalemia and its clinical impact remain to be elucidated in long-term clinical trials. Adverse events of hypotension and episodes of acute deterioration of kidney function were once again rare and balanced across the three study groups [23].

INTERPRETATION OF THE MIRO-CKD RESULTS AND DIRECTIONS FOR FUTURE RESEARCH

The results of the MIRO-CKD trial strengthen the evidence that combination therapy with an SGLT2i and a non-steroidal MRA possibly results in maximal cardiorenal protection in patients with albuminuric CKD. The only large prior study to directly support this notion was the CONFIDENCE (Combination Effect of Finerenone and Empagliflozin in Participants with Chronic Kidney Disease and Type 2 Diabetes Using a Urinary Albumin-to-Creatinine Ratio Endpoint) trial [21]. In this phase 2b trial, 800 patients with albuminuric CKD associated with T2D who were already taking a RAS blocker were randomized in a 1:1:1 ratio to double-blind therapy with finerenone (10–20 mg/day) plus placebo, empagliflozin (10 mg/day) plus placebo, or the combination of empagliflozin plus finerenone. Over 6 months of follow-up, the UACR-lowering effect of combination therapy was 29% greater as compared with finerenone alone and 32% greater as compared with empagliflozin alone [21]. As happened in the MIRO-CKD trial [23], the combination of empagliflozin with finerenone over the course of the CONFIDENCE trial was well tolerated and did not aggravate the risk of serious or unexpected adverse events [21].

MIRO-CKD confirms and expands the prior clinical trial evidence, if we take into consideration that MIRO-CKD included a broader spectrum of patients with CKD who were underrepresented or totally excluded from the CONFIDENCE trial, such as patients with more advanced CKD, CKD of non-diabetic etiology, and CKD patients with higher serum potassium concentrations prior to study enrollment [22]. A key difference between these two trials and a clear methodological limitation of MIRO-CKD is that it did not include a balcinrenone monotherapy arm to enable direct comparisons between combination therapy and balcinrenone alone [21, 23]. Accordingly, MIRO-CKD cannot directly demonstrate the additive UACR-lowering effect of combination therapy relative to the albuminuria-lowering action of either monotherapy.

In a meta-analysis of five trials with 1429 patients (synthesizing data from MIRACLE, MIRO-CKD, and CONFIDENCE) [33], simultaneous initiation of SGLT2i and MRA therapy was associated with 25% greater proportional reduction in UACR as compared to monotherapy with an SGLT2i (95% CI: 18% to 32%) and 20% greater proportional reduction in UACR relative to MRA monotherapy (95% CI: 12% to 27%) [33]. Combination therapy was associated with modestly greater reductions in the levels of eGFR as compared to either therapy alone, but the acute dip in eGFR was more pronounced when SGLT2is were simultaneously initiated with a steroidal than with a non-steroidal MRA [33]. These meta-analytic data further support the potential greater benefits of combination therapy in patients with albuminuric CKD and/or HF.

With respect to the mechanisms implicated in the albuminuria-lowering effect that was observed in the MIRO-CKD trial, relative to monotherapy with dapagliflozin 10 mg/day, the change from baseline in office systolic blood pressure (BP) was −0.4 mmHg (95% CI: −4.4 to 3.3) in the balcinrenone 15 mg/day plus dapagliflozin 10 mg/day group and −2.5 mmHg (95% CI: −6.5 to 1.4) in the balcinrenone 40 mg/day plus dapagliflozin 10 mg/day group [23]. In our opinion, it is unlikely that this modest reduction in systolic BP was the predominant mediator of the treatment-induced improvement in albuminuria. However, the early, acute, and reversible decrease in eGFR observed over the course of the MIRO-CKD trial suggests that intrarenal hemodynamic actions of combination therapy with balcinrenone plus dapagliflozin (i.e. reductions in intra-glomerular pressure) might have played a more important role [23]. Apart from hemodynamically mediated reduction in albuminuria over a short-term treatment period, experimental and preclinical data are also supporting the notion that a long-term kidney protective effect of balcinrenone may be driven by other mechanisms, such as downregulation of inflammatory and fibrotic pathways directly at the kidney level [24, 29, 30].

Finally, the greater reduction in albuminuria observed with the combination of balcinrenone and dapagliflozin compared with dapagliflozin alone in the MIRO-CKD trial provides the rationale for a large, definitive phase 3 clinical trial to determine whether this therapeutic strategy translates into improved “hard” clinical outcomes. An early treatment-induced reduction in albuminuria is a validated surrogate marker for predicting reduced risk of long-term CKD progression. This notion is supported by an updated 2026 meta-analysis of 48 trials (incorporating individual patient-level data from a total of 85 681 participants) showing that an early 30% placebo-corrected reduction in UACR with active treatment is associated with a 19% improvement in the long-term risk of the composite clinical outcome of doubling of serum creatinine or progression of CKD to kidney failure [34]. Additional supportive evidence has been provided by two exploratory analyses of the FIDELIO-DKD (Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease) and FIGARO-DKD (Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease) trials. In the first analysis (involving 12 512 patients), an early MRA-induced reduction in albuminuria mediated 84% of the long-term benefit of finerenone versus placebo on the composite outcome of kidney failure, sustained ≥57% decrease in eGFR from baseline or death attributable to renal causes [35]. In the second analysis (including 12 143 participants in the FIDELIO-DKD and FIGARO-DKD trials), the early reductions in UACR and office systolic BP jointly accounted for half of the long-term benefit of finerenone versus placebo on the composite outcome of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or HF hospitalization [36].

RATIONALE AND DESIGN OF PHASE 3 CLINICAL TRIAL PROGRAM OF BALCINRENONE

Taken together, MIRACLE enrolled predominantly patients with symptomatic HF and failed to show the originally anticipated dose-dependent improvement in albuminuria with the combination of balcinrenone and dapagliflozin versus dapagliflozin alone, possibly due to its premature termination and underpowering as discussed earlier [32]. In contrast, the larger and successfully completed MIRO-CKD trial showed that as compared to monotherapy with dapagliflozin, the combination of balcinrenone plus dapagliflozin resulted in a dose-dependent reduction in UACR in patients with albuminuric CKD [23]. Hopefully, the uncertainly for the benefit–risk ratio of balcinrenone across the whole cardiorenal continuum will be resolved with the results of two ongoing phase 3 clinical trials (Table 2 ). These trials are anticipated to provide stronger and definitive evidence for the safety profile and efficacy of this investigational non-steroidal MRA in a broad spectrum of patients with HF and CKD.

Table 2:

Ongoing phase 3 clinical trials with the investigational non-steroidal MRA balcinrenone in cardiorenal medicine.

Trial	BalanceD-HF (NCT06307652)	BalanceD-CKD (NCT07624305)
Sample size	4800	2800
Study design	Phase 3, international, multicenter, randomized, double-blind, parallel-group, double-dummy, active-controlled, event-driven study	Phase 3, multicenter, randomized, double-blind, double-dummy, parallel-group, active-controlled, event-driven study
Patients	Symptomatic HF and CKD (eGFR: 20–60 ml/min/1.73 m2) with a recent HF event	Moderate-to-advanced CKD with or without significant albuminuria
Intervention	Balcinrenone (15 mg/day) plus dapagliflozin (10 mg/day), balcinrenone (40 mg/day) plus dapagliflozin (10 mg/day), or dapagliflozin (10 mg/day) plus placebo	Balcinrenone (15 mg/day) plus dapagliflozin (10 mg/day), or dapagliflozin (10 mg/day) plus placebo
Time frame	38 months	46 months
Primary efficacy outcome	CV death, HF hospitalization, or HF event without hospitalization	CV death, death due to kidney failure, kidney failure, sustained ≥50 decrease in eGFR levels from baseline or HF event
Expected completion date	June 2027	July 2030

Abbreviations: BalanceD-HF = A phase III Study to Evaluate the Effect of Balcinrenone/​Dapagliflozin in Patients with Heart Failure and Impaired Kidney Function; BalanceD-CKD = A Study to Evaluate the Effect of Balcinrenone/​Dapagliflozin in Patients with CKD Stage 3b and 4; CKD = chronic kidney disease; CV = cardiovascular; eGFR = estimated glomerular filtration rate; HF = heart failure.

In the BalanceD-HF (Study to Evaluate the Effect of Balcinrenone/​Dapagliflozin in Patients with Heart Failure and Impaired Kidney Function) (NCT06307652), 4800 patients with symptomatic HF, CKD (eGFR 20–60 ml/min/1.73 m²), and a recent HF event will be randomized in a 1:1:1 ratio to receive double-blind treatment with the combination of balcinrenone 40 mg/day plus dapagliflozin 10 mg/day, balcinrenone 15 mg/day plus dapagliflozin 10 mg/day, or dapagliflozin 10 mg/day plus placebo. The primary efficacy outcome has been defined as the between-group difference in the time to first occurrence of any of the components of the composite of cardiovascular death, hospitalization due to HF, or HF event without hospitalization. The completion of BalanceD-HF is expected till June 2027.

In the BalanceD-CKD (Study to Evaluate the Effect of Balcinrenone/​Dapagliflozin in Patients with CKD Stage 3b and 4) (NCT07624305), 2800 patients with stage 3b–4 CKD with or without a concomitant diagnosis of T2D will be randomly assigned in a 1:1 ratio to double-blind therapy with the combination of balcinrenone (15 mg/day) plus dapagliflozin (10 mg/day) or dapagliflozin (10 mg/day) with matching placebo. According to the eligibility criteria, all patients will be treated with maximally tolerated doses of a RAS blocker prior to study enrollment, unless contraindicated.

BalanceD-CKD is planning to enroll patients who were truly underrepresented or excluded from prior phase 3 clinical trials with SGLT2is or the non-steroidal MRA finerenone [4–6, 13, 14], such as patients with eGFR ≥15 to <30 ml/min/1.73 m² and without significant albuminuria (UACR <30 mg/g) (Fig. 2). Notably, prior individual trials showed that the benefit of SGLT2is versus placebo was attenuated in the subgroups of patients with stage 4 CKD or in those with little to no albuminuria [5, 6]. However, a 2026 meta-analysis of 10 trials with 70 361 participants from SMART-C (SGLT2 Inhibitor Meta-Analysis Cardio-Renal Trialists’ Consortium) provided evidence supporting the consistency of the kidney protective effect of SGLT2is irrespective of baseline eGFR and albuminuria levels [37]. The investigators of BalanceD-CKD are hypothesizing that balcinrenone will prove easier to use in terms of hyperkalemia risk compared to other MRAs at low eGFR, while providing benefit beyond SGLT2is on a broader composite cardiorenal endpoint than that used in prior large outcome trials [4–6]. Accordingly, the main research question in this ongoing trial is whether the combination of balcinrenone 15 mg/day plus dapagliflozin 10 mg/day is superior to monotherapy with dapagliflozin in lowering the incidence of the prespecified cardiorenal outcome, defined as the composite of cardiovascular death, death attributable to kidney failure, kidney failure, sustained ≥50% decrease in the levels of eGFR from baseline or new-onset HF event. The selection of the lower dose of 15 mg/day for balcinrenone is probably related to pharmacokinetic properties and the benefit–risk ratio in the population under study. It has been assumed that the higher dose of 40 mg/day may offer no significant additive benefit in patients with predominantly advanced (stage 4) CKD. In contrast, there is the assumption that the higher dose may magnify the risk of hyperkalemia-related adverse events, as shown in the MIRO-CKD study (hyperkalemia 13.0% with 40 mg vs. 7.0% with 15 mg vs. 5.0% with placebo) [23]. BalanceD-CKD is anticipated to be completed in July 2030.

Figure 2:

Patient populations according to inclusion values for eGFR and UACR in phase 3 trials investigating the safety and efficacy of different non-steroidal MRAs in patients with CKD. Abbreviations: BalanceD-CKD = A Phase III Study to Evaluate the Effect of Balcinrenone/Dapagliflozin in Patients With CKD Stage 3b and 4; UACR = urinary albumin-to-creatinine ratio; eGFR = estimated glomerular filtration rate; FIDELIO-DKD = Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease; FIND-CKD = Finerenone Non-Diabetic Chronic Kidney Disease; FIGARO-DKD = Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease.

Some questions will remain unanswered, even after successful completion of the ongoing phase 3 clinical trial program of balcinrenone. BalanceD-HF and BalanceD-CKD do not include a steroidal MRA comparator arm. Therefore, a direct comparison of the safety and efficacy of conventional MRAs and balcinrenone is lacking. This evidence gap is also applicable to the non-steroidal MRA finerenone—there are only indirect post hoc analyses comparing spironolactone with finerenone in patients with resistant hypertension and moderate-to-advanced CKD [38, 39]. Furthermore, balcinrenone is being developed as a potential refinement of the currently established MRA pillar (Table 3). For example, exploratory analyses of the MIRO-CKD trial suggest that the majority of hyperkalemic events with balcinrenone occurred predominantly in patients with baseline serum potassium concentrations of ≥4.8 mmol/l (i.e. in patients who were not eligible in finerenone trials) [23]. However, these exploratory data should not be falsely interpreted as a proof that treatment with balcinrenone offers the advantage of a more favorable side effect profile than that of finerenone. Trials with finerenone provided long-term safety data for the accumulated risk of hyperkalemia in CKD patients who were infrequently receiving background treatment with SGLT2is [12–14]. In contrast, MIRO-CKD was a short-term study, in which the SGLT2i dapagliflozin was co-administered with balcinrenone [23]. Accordingly, cross-trial comparisons are unreliable due to differences in clinical characteristics of patients, study duration, background treatment with SGLT2is, etch. Direct and head-to-head comparisons will be needed to explore potential similarities or differences in safety and efficacy of these two non-steroidal MRAs.

Table 3:

Mechanism of action, pharmacokinetic properties, and clinical development stage of the non-steroidal MRAs finerenone and balcinrenone.

Parameter	Finerenone	Balcinrenone
Pharmacological profile
• Agonism/antagonism	• Full antagonist	• Partial agonist
• Cofactor recruitment	• Inverse agonist	• Modulator
Plasma half-life in healthy volunteers	• 2–3 h	• 2–3 h after a single dosing and 4–9 h after 8-day administration
Development stage	• Approved by regulatory agencies with the indication of cardiorenal protection in patients with CKD and T2D as well as in patients with HFpEF	• Investigational
Available efficacy outcome data	• Completed phase 3 trials demonstrating the benefit of finerenone vs. placebo on “hard” clinical outcomes	• Dose-dependent reductions in UACR in patients with CKD and albuminuria
Associated risk of hyperkalemia	• Low incidence of treatment-emergent hyperkalemia leading to permanent discontinuation of therapy	• Small and dose-dependent elevations in serum potassium levels over 3 months of treatment • The accumulated risk of hyperkalemia and its clinical impact remain to be determined

Abbreviations: CKD = chronic kidney disease; HFpEF = heart failure with preserved ejection fraction; T2D = type 2 diabetes; UACR = urinary albumin-to-creatinine ratio.

CONCLUSION

In conclusion, overactivity of the MR is an attractive and mechanistically plausible target of therapy offering cardiorenal protection in patients with cardio-kidney-metabolic diseases. Balcinrenone is a novel, non-steroidal MRA with distinct mechanisms of actions from that mediating the effects of traditional steroidal MRAs, such as spironolactone and eplerenone. In the MIRO-CKD, combination therapy with balcinrenone and dapagliflozin was more effective than dapagliflozin alone in reducing albuminuria over a follow-up period of 12 weeks [23]. Apart from evidence for the efficacy, the MIRO-CKD trial also provided data supporting a favorable side effect profile of this intervention [23]. These preliminary data provide the rationale for the design of a large phase 3 clinical trial program aiming to elucidate the safety and efficacy of balcinrenone in a broad spectrum of patients with cardio-kidney-metabolic diseases. If the results of these two ongoing phase 3 trials are positive, our therapeutic toolkit for maximal cardiorenal protection will become broader. The successful implementation of these novel therapies will depend on addressing their potentially substantial costs and limited accessibility, which may otherwise exacerbate inequalities in treatment access and place additional financial pressures on healthcare systems.

AUTHORS’ CONTRIBUTIONS

P.I.G., S.S., and C.K. reviewed the literature and drafted the initial version of the manuscript. E.D. V.L., and P.B.M reviewed the literature and edited the manuscript. All authors have read and approved the final version of the manuscript.

CONFLICT OF INTEREST STATEMENT

P.I.G., C.K., S.S., E.D., and V.L. have no conflicts of interest relevant to this work to disclose; P.B.M. received grants from AstraZeneca, consulting fees from AstraZeneca, Pharmacosmos, and Vifor, honoraria for lectures from AstraZeneca, Boehringer Ingelheim, and Vifor, and participates in data monitoring boards for Vertex and Boehringer Ingelheim

FUNDING

No external funds were used in the preparation of this manuscript.

DATA AVAILABILITY STATEMENT

No new data were generated in this manuscript.