Review Article

The Emerging Role of Aldosterone Synthase Inhibitors in Overcoming Renin– Angiotensin–Aldosterone System Therapy Limitations: A Narrative Review

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Abstract

The renin–angiotensin–aldosterone system is integral to cardiorenal health, with aldosterone controlling fluid balance, blood pressure and cardiac remodelling. Despite the widespread use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and mineralocorticoid receptor antagonists, ‘aldosterone escape’ persists, contributing to treatment failure and adverse outcomes. Steroidal mineralocorticoid receptor antagonists also cause hyperkalaemia and anti-androgenic effects, limiting their use. Aldosterone synthase inhibitors (ASIs) selectively block cytochrome P450 11B2, reducing pathological aldosterone levels while preserving basal mineralocorticoid receptor activity, thus potentially lowering hyperkalaemia risk. This narrative review identified 41 relevant publications from a PubMed/MEDLINE search of “aldosterone synthase inhibitor” through 11 January 2025. Early clinical trials of ASIs (baxdrostat, lorundrostat, vicadrostat, dexfadrostat phosphate, JX09) report significant reductions in aldosterone, blood pressure and albuminuria, with promising safety. Challenges include ensuring high selectivity, mitigating hyperkalaemia and establishing long-term benefits. Ongoing Phase III trials will clarify their efficacy, safety and synergy with additional therapies – including sodium–glucose cotransporter 2 inhibitors – and clinical outcomes, positioning ASIs as an important advance in renin– angiotensin–aldosterone system modulation.

Keywords

Aldosterone synthase inhibitors, aldosterone, hypertension, mineralocorticoid receptor, renin–angiotensin–aldosterone system,

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Published online:

DOI: https://doi.org/10.15420/cfr.2025.09

Disclosure: HT has received personal fees from the Canadian Medical and Surgical Knowledge Translation Research Group. TMY has consulting relationships with Abbott, Medtronic, Gore, Bluerock Therapeutics, Novo Nordisk, Aziyo Therapeutics and Salutech. SV has received grants, research support and honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, the Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Humber River Health, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, S&L Solutions, Sanofi; and is the President of the Canadian Medical and Surgical Knowledge Translation Research Group. All other authors have no conflicts of interest to declare.

Acknowledgements: SV holds a Tier 1 Canada Research Chair in Cardiovascular Surgery.

Correspondence: Subodh Verma, Division of Cardiac Surgery, 8th Floor, Bond Wing, St Michael’s Hospital, 30 Bond St, Toronto, Ontario, M5B 1W8, Canada. E: subodh.verma@unityhealth.to

Copyright:

© The Author(s). This work is open access and is licensed under CC-BY-NC 4.0. Users may copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Although dysregulation of the renin–angiotensin–aldosterone system (RAAS) is critical to the pathogenesis of cardiorenal disease, the RAAS is and continues to be a preferred target of many traditional and emerging cardiorenal therapies. Central to the RAAS is aldosterone, a mineralocorticoid hormone produced in the adrenal cortex, which regulates fluid and electrolyte balance, blood pressure and cardiac remodelling.1–5 RAAS-targeting pharmacotherapies include angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and mineralocorticoid receptor antagonists (MRAs), all of which have significantly improved the management and control of hypertension, chronic kidney disease (CKD) and heart failure.

Despite these advancements, many users of RAAS inhibitors experience a phenomenon known as ‘aldosterone escape’ whereby circulating aldosterone levels are paradoxically and chronically elevated.6 Aldosterone escape, discussed in detail later on in this review, has been a driving force for the renewed interest in identifying approaches that target aldosterone synthesis through the inhibition of aldosterone synthase (cytochrome P450 [CYP] 11B2).

Aldosterone synthase inhibitors (ASIs) are novel and promising therapeutic options that address the limitations of traditional RAAS blockade by targeting the enzyme responsible for aldosterone biosynthesis.7,8 ASIs mitigate the genomic and non-genomic effects of aldosterone by lowering circulating aldosterone levels. Unlike MRAs that function downstream by binding to mineralocorticoid receptors (MRs), ASIs intervene at the source, potentially preserving basal MR activity mediated by glucocorticoids in non-aldosterone-sensitive tissues.9 This distinct site of action may translate to less risk of hyperkalaemia – a common MRA-associated adverse effect – and concomitantly prevent the compensatory aldosterone elevations that often accompany chronic MRA use.10

Early clinical trials of ASIs have demonstrated encouraging results, with several agents showing effective reductions in aldosterone levels, improvements in blood pressure and favourable safety profiles.11,12 Moreover, preclinical and mechanistic studies suggest that ASIs may have broader anti-inflammatory and antifibrotic benefits that may help address the pathological remodelling of cardiovascular structures that are associated with aldosterone excess. These attributes position ASIs as a compelling addition to the therapeutic paradigm for heart failure, CKD and other aldosterone-driven conditions.

This review explores the physiology and pathophysiology of aldosterone, the limitations of existing RAAS-modulating therapies, and the development of ASIs as an innovative therapy. By integrating evidence from preclinical studies and clinical trials, we aim to lend credence to the potential of ASIs as a valuable addition to the current cardiorenal care toolbox.

Literature Search

A search of PubMed/MEDLINE from inception through to 11 January 2025, was performed using the key term “aldosterone synthase inhibitor”. This search yielded 598 publications from 1986 to 2024. Articles were screened by title and abstract for relevance to the topic, and 41 full-text English-language articles were selected for inclusion. SKP independently evaluated and selected studies based on their focus on the limitations of existing treatments and the mechanisms, development, clinical evidence and future directions of ASIs.

Aldosterone Synthesis and Regulation

Enzymatic Pathway

Aldosterone, the principal mineralocorticoid hormone, is synthesised in the zona glomerulosa of the adrenal cortex through a tightly regulated enzymatic cascade (Figure 1).1–3,13–15 The final and rate-limiting step of aldosterone biosynthesis is catalysed by CYP11B2, a cytochrome P450 enzyme that is localised to the mitochondrial inner membrane.15 CYP11B2 mediates the sequential hydroxylation and oxidation of 11-deoxycorticosterone to corticosterone, 18-hydroxycorticosterone and ultimately aldosterone.16,17

Figure 1: Overview of the Adrenal Gland Structure, Steroidogenesis Pathways and the Role of Aldosterone Synthase Inhibitors in Modulating Aldosterone Production

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Aldosterone synthase shares substantial genetic and structural homology with 11β-hydroxylase (CYP11B1), an enzyme that is primarily expressed in the zona fasciculata and zona reticularis, where it facilitates cortisol synthesis. CYP11B2 and CYP11B1 exhibit 95% sequence homology in coding regions and have identical enzymatic active sites.18–20 Despite the similarities, these enzymes are functionally distinct, as CYP11B1 cannot catalyse the aldosterone-specific oxidation step. The close genomic proximity of CYP11B2 and CYP11B1 on chromosome 8q21, along with their overlapping functions, underscores the challenges in selectively targeting aldosterone synthesis without disrupting cortisol production.

The regulation of aldosterone synthesis is multifaceted, with angiotensin II, extracellular potassium levels and adrenocorticotropic hormone serving as the primary modulators.4 Angiotensin II, acting through angiotensin II receptor type 1, is a key driver of aldosterone production in response to hypovolaemia or decreased sodium delivery sensed by the macula densa.4,5,21 Angiotensin II stimulates CYP11B2 transcription through calcium-dependent signalling pathways, culminating in increased aldosterone output.22–24 Elevated extracellular potassium directly depolarises adrenal zona glomerulosa cells, triggering calcium influx and subsequent CYP11B2 activation. Adrenocorticotropic hormone exerts a more transient stimulatory effect via cyclic adenosine monophosphate pathways and melanocortin receptor 2.25,26 Together, these regulatory mechanisms maintain precise control over aldosterone synthesis to balance fluid and electrolyte homeostasis.

Physiological Impact of Aldosterone

Aldosterone exerts its physiological effects predominantly in the aldosterone-sensitive distal nephron, encompassing the late distal tubule, connecting tubule and collecting duct.27,28 Through its action on epithelial sodium channels in these nephron segments, aldosterone facilitates sodium reabsorption, promoting water retention and increasing extracellular fluid volume and blood pressure.28–31 Simultaneously, aldosterone enhances potassium excretion via potassium channels, including the renal outer medullary potassium channel and big potassium channel, ensuring potassium homeostasis.28,30,32 Aldosterone also plays a critical role in regulating acid-base balance through its control of hydrogen ion excretion during states of acidosis via intercalated cells in the distal nephron.33 Type A intercalated cells increase proton secretion in response to aldosterone, while non-type A cells upregulate bicarbonate excretion through the anion exchanger pendrin.33,34

Pathophysiology of Excess Aldosterone

Excess aldosterone production or activity contributes to a myriad of significant cardiovascular, renal and metabolic pathologies (Figure 2).35,36 The binding of aldosterone to cytoplasmic MRs leads to their nuclear translocation and subsequent modulation of target gene expression.27 Specifically, this genomic pathway drives the synthesis of epithelial sodium channels subunits, serum- and glucocorticoid-regulated kinase 1 and Na+/K+-ATPase.28,32

Figure 2: The Pathological Consequences of Excess Aldosterone and Potential Therapeutic Applications of Aldosterone Synthase Inhibitors

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Aldosterone also induces rapid non-genomic effects that are independent of MR activation.37 These effects include increases in intracellular calcium levels, activation of NADPH oxidase and elevations in reactive oxygen species production.37–39 Emerging evidence suggests that non-genomic effects of aldosterone may be mediated by alternative receptors, such as the G protein-coupled oestrogen receptor and the insulin-like growth factor-1 receptor.40–42 Activation of these receptors can exacerbate aldosterone-induced oxidative stress, inflammation and fibrosis, amplifying the pathological impact of aldosterone.

Excess aldosterone has further been implicated in a spectrum of cardiovascular pathologies, among which are myocardial fibrosis, vascular stiffness, endothelial dysfunction and glomerulosclerosis.27,35,43–45 In the heart, aldosterone promotes myofibroblast proliferation, upregulates transforming growth factor-β and drives extracellular matrix remodelling, contributing to diastolic dysfunction and left ventricular hypertrophy.46,47 In the vasculature, aldosterone-induced release of reactive oxygen species and pro-inflammatory cytokines, such as C-reactive protein and interleukin-6, enhances vascular inflammation and fibrosis, predisposing to hypertension and arterial remodelling.9,48,49 Finally, in the kidneys, aldosterone accelerates proteinuria, tubulointerstitial fibrosis and CKD progression through MR-dependent and independent pathways.45,50–52

Conditions Associated with Hyperaldosteronism

Primary aldosteronism (PA) is a common yet underdiagnosed condition characterised by autonomous aldosterone overproduction, typically resulting from adrenal adenomas or bilateral adrenal hyperplasia.53,54 PA affects approximately 5–10% of individuals living with hypertension and is the most common cause of secondary hypertension.55 Despite its prevalence, PA remains under-recognised, with many cases often misattributed to essential hypertension.56 This diagnostic gap delays effective intervention, allowing aldosterone-mediated organ damage to progress.

PA is notably associated with elevated levels of pro-inflammatory markers, including tumour necrosis factor-alpha, interleukin-6 and C-reactive protein, all of which correlate with the systemic effects of PA.57 Hyperaldosteronism is also linked to increased risk of cardiovascular events that include MI, AF and stroke.58 Beyond PA, aldosterone excess is frequently observed in conditions, such as heart failure, liver cirrhosis and renal artery stenosis, where chronic RAAS activation perpetuates aldosterone-driven pathology.59–61

Challenges with Existing Therapies

Steroidal Mineralocorticoid Receptor Antagonists

MRAs, such as spironolactone and eplerenone, have been essential for decreasing complications and outcomes among people living with heart failure and other aldosterone-related conditions (Table 1). In the randomised, double-blind, placebo-controlled RALES trial, 1,663 patients with severe heart failure (New York Heart Association [NYHA] class III or IV) and a left ventricular ejection fraction of no more than 35% – all of whom were receiving an ACE inhibitor, a loop diuretic and (in most cases) digoxin – were enrolled. The study demonstrated a 30% reduction in mortality among those treated with 25 mg of spironolactone daily.62

Table 1: Comparative Overview of Steroidal Mineralocorticoid Receptor Antagonists, Nonsteroidal Mineralocorticoid Receptor Antagonists and Aldosterone Synthase Inhibitors

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The multicentre, international, randomised, double-blind, placebo-controlled EPHESUS trial randomised 6,632 post-MI patients with left ventricular dysfunction (ejection fraction ≤40%) and clinical signs of heart failure to receive either eplerenone (25 mg daily, titrated up to 50 mg; n=3,313) or placebo (n=3,319) in addition to optimal medical therapy. This study showed a survival benefit with a 15% relative reduction in all-cause mortality (14.4% versus 16.7%; RR 0.85; p=0.008) and a significant 17% reduction in cardiovascular mortality (12.3% versus 14.6%; RR 0.83; p=0.005).63

The EMPHASIS-HF trial, which randomised 2,737 patients with chronic systolic heart failure (NYHA class II) and a left ventricular ejection fraction of no more than 35% – all of whom were receiving recommended therapies – to receive eplerenone (up to 50 mg daily) or placebo demonstrated a 37% relative reduction in the composite endpoint of death from cardiovascular causes or hospitalisation for heart failure (18.3% versus 25.9%; HR 0.63; 95% CI [0.54–0.74]; p<0.001) and a significant reduction in all-cause mortality (12.5% versus 15.5%; HR 0.76; 95% CI [0.62–0.93]; p=0.008).64

Despite their overall efficacy, the use of steroidal MRAs has been limited by their clinically significant adverse effects. Spironolactone, derived from progesterone analogues, is associated with anti-androgenic effects including gynecomastia, impotence and menstrual irregularities.65 These adverse effects are dose-dependent and are often associated with nonadherence and discontinuation.

Hyperkalaemia is another common concern, particularly among those living with CKD and those who are on concomitant RAAS inhibitors.66 The risk of hyperkalaemia is notably heightened in populations that are most likely to benefit from MRAs, such as people living with advanced heart failure or CKD, creating a therapeutic paradox that limits their utility.

Steroidal MRAs do not have any effect on the non-genomic actions of aldosterone.67 Therefore, these rapid, non-transcriptional pathways, implicated in oxidative stress, fibrosis and inflammation, persist even with MRA therapy. This limitation highlights the need for alternative therapeutic strategies that target aldosterone synthesis at its source rather than solely antagonising its receptor.

Nonsteroidal Mineralocorticoid Receptor Antagonists

Nonsteroidal MRAs, such as finerenone and esaxerenone, represent a major step forward in addressing some of the limitations of steroidal MRAs. Finerenone, a selective nonsteroidal MRA, has demonstrated significant benefits in individuals with heart and kidney complications.

The randomised, double-blind, placebo-controlled, parallel-group, multicentre, event-driven Phase III FIDELIO-DKD trial randomised 5,734 patients with type 2 diabetes and CKD (estimated glomerular filtration rate [eGFR] 25 to <75 ml/min/1.73 m2 and a urinary albumin-to-creatinine ratio [UACR] of 30–5,000 mg/g) who were already receiving maximally tolerated renin–angiotensin system blockade drugs to receive either finerenone or placebo. FIDELIO-DKD showed that finerenone lowered the risk of CKD progression (17.8% versus 21.1%; HR 0.82; 95% CI [0.73–0.93]; p=0.001) and cardiovascular events (13.0% versus 14.8%; HR 0.86; 95% CI [0.75–0.99]; p=0.03).68 The randomised, double-blind, placebo-controlled, parallel-group, multicentre, event-driven Phase III FIGARO-DKD trial randomised 7,437 patients with type 2 diabetes and CKD (eGFR 25–90 ml/min/1.73 m² and UACR 30–5,000 mg/g) to receive finerenone or placebo in addition to drugs that block the renin–angiotensin system. FIGARO-DKD revealed that finerenone assignment significantly lowered the risk of the primary composite outcome of death from cardiovascular causes, nonfatal MI, nonfatal stroke, or hospitalisation for heart failure (12.4% versus 14.2%; HR 0.87; 95% CI [0.76–0.98]; p=0.03) that was primarily driven by the significant 29% reduction in hospitalisation for heart failure (HR 0.71; 95% CI [0.56–0.90]).69

Esaxerenone has also shown promise, particularly in reducing albuminuria in patients with diabetic nephropathy. The Phase III multicentre, randomised, double-blind ESAX-DN trial enrolled 455 patients with type 2 diabetes and a UACR of 45 to <300 mg/g who were treated with renin–angiotensin system inhibitors. Esaxerenone, compared with placebo, significantly increased the proportion of patients achieving UACR remission (22% versus 4%; p<0.001) and reduced UACR by 58% versus an 8% increase with placebo.70 In the Phase III multicentre, randomised, ESAX-HTN study (NCT02890173), 1,001 patients with essential hypertension were enrolled. Esaxerenone (2.5 mg/day) was noninferior to eplerenone in reducing both sitting and 24-hour blood pressure.71 Furthermore, esaxerenone (5 mg/day) achieved significantly greater blood pressure reductions and a higher proportion of patients reached the target blood pressure (<140/90 mmHg) compared with eplerenone (41.2% versus 27.5%).

Nonsteroidal MRAs are not without challenges. Like steroidal MRAs, nonsteroidal MRAs carry a significant risk of hyperkalaemia, particularly in people living with CKD or those who are on concurrent RAAS inhibitors.72 While finerenone has demonstrated a lower propensity for hyperkalaemia than spironolactone or eplerenone due to reduced tissue penetration, the risk remains substantial, particularly in clinical scenarios involving impaired renal potassium excretion. Additionally, the long-term efficacy of nonsteroidal MRAs in addressing the non-genomic effects of aldosterone remains uncertain, necessitating further investigation.

Aldosterone Escape Phenomenon

‘Aldosterone escape’ describes the resurgence of circulating aldosterone levels in patients who are on chronic RAAS inhibitor therapy (Figure 3). This phenomenon is the eventual manifestation of various occurrences. Although ACE inhibitors and ARBs effectively reduce the synthesis of angiotensin II and its downstream effects, compensatory activation of alternative enzymatic pathways that involve chymase and cathepsin G can lead to ACE-independent generation of angiotensin II.73–77 Chymase, expressed predominantly in cardiovascular tissues, directly converts angiotensin I to angiotensin II, circumventing ACE inhibitors’ blockade and stimulating CYP11B2 transcription to elevate aldosterone levels chronically.73–77 Additionally, hyperkalaemia – often induced by chronic RAAS blockade – triggers direct adrenal zona glomerulosa stimulation, further exacerbating aldosterone production through calcium-dependent pathways.78 Local tissue activation of RAAS components can also elevate aldosterone levels.73,74,79

Figure 3: Mechanistic Overview of the Aldosterone Escape Phenomenon

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The heightened levels of aldosterone promote sodium and fluid retention, increase preload and afterload, raise blood pressure, promote oedema, worsen heart failure and elevate oxidative stress and inflammation, thereby perpetuating progressive cardiovascular and kidney damage.35,80,81 Moreover, aldosterone escape exacerbates myocardial and vascular fibrosis through both genomic and non-genomic pathways.35,36 Aldosterone-driven fibrosis is mediated via the transforming growth factor-β pathway and involves collagen synthesis and matrix remodelling, which collectively lead to myocardial stiffness, diastolic dysfunction and progressive heart failure.44,82,83 Vascular inflammation and endothelial dysfunction, potentiated by chronic aldosterone exposure, elevate cardiovascular risk by increasing arterial stiffness and accelerating atherosclerosis.84 Evidence from trials, such as RALES and EMPHASIS-HF, indicates that persistent aldosterone activity, despite RAAS inhibition, contributes to residual cardiovascular risk.62,64 In the kidneys, persistent aldosterone elevations induce glomerular sclerosis, interstitial fibrosis and proteinuria, thereby accelerating the progression towards CKD and treatment-resistant hypertension.27,85

Development of Aldosterone Synthase Inhibitors

Mechanistic Rationale for Aldosterone Synthase Inhibitors

ASIs act at the enzymatic source of aldosterone production by selectively inhibiting CYP11B2, the final catalyst in aldosterone biosynthesis (Figure 1).8,86 Accordingly, they suppress both circulating and tissue aldosterone, curbing the genomic (pro-fibrotic and pro-inflammatory gene transcription) and non-genomic (oxidative stress, inflammation, endothelial dysfunction) effects of aldosterone.9,87 Because their actions occur downstream of renin and angiotensin II, ASIs bypass compensatory pathways – such as chymase-mediated angiotensin II generation – that undermine ACE inhibitors and ARBs, and they prevent the aldosterone-escape phenomenon that can also arise during long-term MRA therapy.88,89 Unlike MRAs, ASIs do not block the mineralocorticoid receptor itself; thus, physiological receptor activation – largely sustained by endogenous glucocorticoids – remains intact, which reduces the risk of hyperkalaemia.9 Nonetheless, achieving high selectivity for CYP11B2 over the structurally similar CYP11B1 enzyme remains a key challenge in ASI development.90

Imidazole-based Inhibitors: Fadrozole

Early efforts to develop ASIs focused on imidazole-based compounds, such as fadrozole, initially studied as an aromatase inhibitor for breast cancer therapy.8 Fadrozole demonstrated the ability to inhibit CYP11B2, reducing plasma and urine aldosterone levels in preclinical models. However, its poor selectivity for CYP11B2 over CYP11B1 (selectivity ratio ~6) and the resulting suppression of cortisol synthesis limited its clinical viability. Despite these shortcomings, fadrozole provided valuable insights into the design of more selective CYP11B2 inhibitors.

Osilodrostat

Building on the structure of fadrozole, osilodrostat emerged as a potent CYP11B2 inhibitor with improved pharmacokinetics.8,9 A multicentre, randomised, double-blind, placebo and active controlled, parallel group, dose finding Phase II trial (NCT00758524) demonstrated dose-dependent reductions in aldosterone levels and modest blood pressure improvements in hypertensive patients (Table 2).91 However, osilodrostat also significantly inhibited CYP11B1, leading to elevated levels of steroid intermediates such as 11-deoxycorticosterone, which has intrinsic mineralocorticoid activity.92,93 These off-target effects contributed to limited efficacy in blood pressure reduction at higher doses and raised safety concerns, including hypothalamic–pituitary–adrenal axis suppression. Osilodrostat has since been repurposed and approved for Cushing’s disease but is no longer pursued as an ASI for cardiovascular and renal indications.94

Table 2: Clinical Trial Data for Current Aldosterone Synthase Inhibitors in Development

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Table 2: Cont.

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Prominent Aldosterone Synthase Inhibitors in Development

Several selective ASIs are currently under clinical investigation, with early-phase trials indicating promising efficacy and safety profiles. This section highlights their development and key clinical findings to date.

Baxdrostat

Baxdrostat (CIN-107/RO6836191) is a second-generation ASI notable for its >100-fold selectivity for CYP11B2 over CYP11B1.95 It exhibits favourable pharmacokinetics (once-daily oral dosing, rapid absorption and a 30-hour plasma half-life). Early-phase studies in healthy volunteers demonstrated a robust, dose-dependent suppression of aldosterone without altering cortisol levels.95,96

The BrigHTN trial (NCT04519658) marked the first major evaluation of baxdrostat in resistant hypertension. In this randomised, double-blind, placebo-controlled, dose-ranging study, 275 participants – each on three or more antihypertensives (including a diuretic) – were randomised to baxdrostat (0.5, 1, or 2 mg once daily) or placebo.97 Baxdrostat produced dose-dependent reductions in systolic blood pressure (SBP), with placebo-corrected changes of −3.2, −8.1 and −11.0 mmHg for the 0.5, 1 and 2 mg doses, respectively (p<0.05 for the 1 and 2 mg groups). Decreases in serum and urinary aldosterone confirmed aldosterone synthase inhibition, while no significant effects on cortisol levels or adrenal insufficiency were observed. Hyperkalaemia was infrequent, occurring in two patients (1.6%) in the highest dose group, and was reversible upon discontinuation or dose adjustment.

Subsequently, the recently presented HALO trial (NCT05137002) investigated the potential of baxdrostat (0.5, 1 or 2 mg) in uncontrolled hypertension on up to two background medications.98 In this double-blind, placebo-controlled, multicentre study, 249 participants were randomised to active drug or placebo. Unlike BrigHTN, the HALO trial did not demonstrate a significant reduction in SBP (placebo-corrected changes: −0.5, +0.6 and −3.2 mmHg for the 0.5, 1 and 2 mg doses, respectively; all p>0.05). Investigators attributed this lack of significant effect to a larger-than-expected placebo response and nonadherence, with low plasma drug levels observed in some participants. However, baxdrostat dose-dependently reduced serum aldosterone and increased plasma renin activity, consistent with effective aldosterone synthase inhibition. No serious drug-related adverse events were reported and the overall safety profile was favourable.

There are currently many on-going trials that are focused on evaluating the potential of baxdrostat as an antihypertensive agent. The randomised, double-blind, placebo-controlled Phase II FigHTN-CKD trial (NCT05432167) assessed the effects in 194 patients with albuminuric CKD and uncontrolled hypertension. The study focused on changes in mean SBP at 26 weeks, along with secondary renal outcomes, with results to be reported (Table 3).

Table 3: Future and Ongoing Clinical Trials Investigating Aldosterone Synthase Inhibitors

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The recently completed multicentre, open-label Phase II Spark-PA trial (NCT04605549) enrolled 15 patients with PA and uncontrolled hypertension. The study aims to determine the ability of baxdrostat to lower blood pressure and improve potassium levels in this high-risk population.

Phase III trials – Bax24 (NCT06168409) and BaxHTN (NCT06034743) – are under way to confirm the long-term safety and blood-pressure-lowering efficacy of baxdrostat in resistant and uncontrolled hypertension. Bax24 is a multicentre, randomised, double-blind, placebo-controlled, parallel-group Phase III trial that has enrolled 217 patients with resistant hypertension. Participants had a seated SBP of ≥140 mmHg at screening and a mean ambulatory SBP of ≥130 mmHg at baseline despite being on a stable regimen of three or more antihypertensive agents, including a diuretic. The primary endpoint is the change from baseline in ambulatory 24-hour average SBP at 12 weeks. BaxHTN is a multicentre, randomised, double-blind, placebo-controlled, parallel-group Phase III trial that has enrolled 796 patients with hypertension. The cohort includes individuals with uncontrolled hypertension despite being on a stable regimen of two antihypertensive agents (including a diuretic) or treatment-resistant hypertension despite taking three or more antihypertensive agents (including a diuretic). The primary endpoint is the change from baseline in seated SBP at 12 weeks for both 1 mg and 2 mg doses of baxdrostat. An on-going Phase III, randomised, double-blind, active-controlled trial (NCT06268873) is assessing baxdrostat plus dapagliflozin in ~2,500 patients with CKD (eGFR ≥30 and <90 ml/min/1.73 m2) and hypertension (SBP ≥130 mmHg) to explore potential cardiorenal synergism.

If confirmed in larger, longer-duration trials, the selective inhibition of CYP11B2 with baxdrostat and without appreciable cortisol suppression could represent a major advancement in the management of resistant hypertension and related cardiorenal disorders.

Lorundrostat

Lorundrostat (MLS-101) is another second-generation ASI that has >300-fold selectivity for aldosterone synthase relative to 11β-hydroxylase, thus preserving cortisol synthesis while lowering aldosterone.95 It is rapidly absorbed (time to peak ~2 hours) and has a shorter half-life of 8–10 hours, allowing once- or twice-daily dosing. Early-phase trials showed effective aldosterone suppression without significant changes in cortisol or cosyntropin stimulation tests.99

Target-HTN (NCT05001945) offered critical insights into the efficacy and safety of lorundrostat in patients with uncontrolled hypertension. This multicentre, randomised, double-blind, placebo-controlled, dose-ranging Phase II trial enrolled 200 participants who were on at least two antihypertensive medications.99 Lorundrostat was tested at various doses (12.5, 50 or 100 mg once daily and 12.5 or 25 mg twice daily) against placebo. Significant placebo-corrected reductions in systolic automated office blood pressure were observed with 50 mg (−9.6 mmHg) and 100 mg (−7.8 mmHg) once-daily doses. The 50 mg dose also reduced diastolic systolic automated office blood pressure by −5.5 mmHg compared with placebo. Serum aldosterone levels decreased across all active arms, while plasma renin activity rose, consistent with selective aldosterone synthase inhibition. Hyperkalaemia (≥6.0 mmol/l) occurred in 3.6% of participants but resolved with dose adjustment or discontinuation. No cases of adrenal insufficiency were reported and the safety profile was favourable, particularly with the 50 mg once-daily dose.

The randomised, double-blind, placebo-controlled, parallel arm, multicentre Phase II Advance-HTN trial (NCT05769608) provided additional data. This randomised, double-blind, placebo-controlled, parallel arm, multicentre Phase II trial evaluated lorundrostat in 285 participants with uncontrolled or treatment-resistant hypertension.100 Participants were randomised to receive lorundrostat 50 mg daily, lorundrostat 50 mg with potential escalation to 100 mg daily, or placebo, after a standardised antihypertensive regimen. After 12 weeks, lorundrostat reduced 24-hour average SBP by 15.4 mmHg in the stable-dose group and 13.9 mmHg in the dose-adjustment group, compared with 7.4 mmHg in the placebo group. Placebo-adjusted reductions were −7.9 and −6.5 mmHg, respectively. Hyperkalaemia (>6.0 mmol/l) occurred in 5 and 7% of participants receiving lorundrostat, respectively, but no serious adverse events were reported.

Encouraged by these outcomes, the randomised, double-blind, placebo-controlled, parallel-arm, multicentre Phase III Launch-HTN trial (NCT06153693) evaluated the efficacy of lorundrostat in 1,083 patients with uncontrolled or resistant hypertension. Launch-HTN reported that lorundrostat 50 mg once daily lowered automated office SBP by a least-squares mean of 16.9 mmHg at 6 weeks versus 7.9 mmHg with placebo (placebo-adjusted −9.1 mmHg; p<0.001), an effect that was sustained through 12 weeks. Treatment discontinuation attributable to hyperkalaemia, hyponatraemia or a decline in renal function occurred in <1 % of participants.101

A randomised, crossover, double-blind, placebo-controlled Phase II trial (NCT06150924) evaluated the combined potential of lorundrostat and sodium–glucose cotransporter 2 (SGLT2) inhibitors to treat hypertension in 60 patients with hypertension and mild to severe CKD with albuminuria, with results expected soon. These efforts will clarify lorundrostat’s place in managing aldosterone-mediated cardiometabolic disease, particularly for those intolerant or unresponsive to traditional MRAs.

Vicadrostat

Vicadrostat (BI690517) is another highly selective ASI under development for CKD and cardiometabolic risk reduction. In a multinational, randomised, double-blind, placebo-controlled, parallel-dose group Phase II trial (NCT05182840), 586 patients (eGFR ≥30 to ≤90 ml/min/1.73 m²; UACR 200–5,000 mg/g) receiving maximally tolerated RAAS blockade with or without SGLT2 inhibitors (empagliflozin) were initially randomised to receive empagliflozin 10 mg or placebo for 8 weeks.102 Participants were then re-randomised to vicadrostat (3, 10 or 20 mg once daily) or placebo for an additional 14 weeks. Vicadrostat monotherapy lowered albuminuria by up to 39% compared with placebo, and up to 46% in combination with empagliflozin, suggesting additive efficacy. It also produced modest SBP reductions (4–6 mmHg) that increased when co-administered with empagliflozin (7–8 mmHg). Serum potassium rose at higher vicadrostat doses, though concurrent empagliflozin helped mitigate hyperkalaemia. Cortisol levels remained largely unaffected, although mild off-target inhibition of 11β-hydroxylase (evidenced by elevated 11-deoxycortisol) was noted and rare cases of adrenal insufficiency were reported. Minimal eGFR declines (3-5 ml/min/1.73 m²) were observed, consistent with known haemodynamic shifts under RAAS-targeted therapies.

Motivated by these promising findings, the multicentre, international, randomised, double-blind, placebo-controlled Phase III EASi-KIDNEY trial (NCT06531824) will enrol ~11,000 patients with CKD to evaluate the long-term ability of vicadrostat to reduce kidney disease progression, heart failure hospitalisations and cardiovascular mortality when added to standard care (including SGLT2 inhibition). Another double-blind, randomised, parallel-group superiority Phase III trial, EASi-HF (NCT06424288), will assess time to first event of cardiovascular death or hospitalisation for heart failure for vicadrostat plus empagliflozin in ~6,000 patients with heart failure and a left ventricular ejection fraction of ≥40%. These large-scale, event-driven studies will determine whether aldosterone synthase inhibition translates into kidney and cardiovascular benefits surpassing those of current therapies.

Dexfadrostat Phosphate

Dexfadrostat phosphate (DP-13) emerges from a proprietary enantioselective crystallisation process that confers 99.9% enantiomeric excess, enhancing selectivity for CYP11B2 over related steroidogenic enzymes such as CYP11B1.95,103,104 In healthy-volunteer studies, dexfadrostat (1–16 mg daily) showed dose-dependent suppression of aldosterone and mild increases in corticosterone. At ≥16 mg/day, partial inhibition of cortisol production indicated off-target CYP11B1 blockade. Pharmacokinetic analyses revealed rapid absorption (~2 hours to peak) and an elimination half-life of ~9.5–11 hours.

A recent multicentre, randomised, double-blind, parallel group, baseline- and withdrawal-controlled trial (NCT04007406) enrolled 36 adults with PA and assigned 35 to one of three once-daily dexfadrostat regimens (4, 8 or 12 mg) for 8 weeks.105 Despite the absence of a parallel placebo arm, significant reductions in aldosterone-to-renin ratio were observed across all treatment groups (median aldosterone–to–renin ratio: 15.3–0.6; 92.1% relative reduction; p<0.0001) and 24-hour ambulatory SBP (142.6–131.9 mmHg; least-squares mean change: −10.7 mmHg; p<0.0001). Declines in aldosterone and urinary tetrahydroaldosterone were accompanied by compensatory increases in plasma 11-deoxycorticosterone and corticosterone, reflecting selective CYP11B2 inhibition. The trial reported no cases of hyperkalaemia or adrenal insufficiency, with mean plasma potassium levels remaining within the normal range and cortisol levels stable throughout. Treatment-emergent adverse events were mild to moderate, most commonly gastrointestinal disturbances and headaches, with no severe or serious adverse events. These results highlight dexfadrostat’s efficacy and tolerability in treating PA; however, larger-scale, longer-duration trials are essential to validate its efficacy and further assess safety.

JX09

JX09 (formerly PB 6440) is a novel ASI from China characterised by its markedly high selectivity for CYP11B2 – surpassing 300-fold relative to CYP11B1.106 This selectivity profile exceeds that of other ASIs, such as baxdrostat (<100-fold).95 Preliminary primate studies demonstrated >90% reductions in aldosterone with JX09, without the significant accumulation of steroid precursors sometimes noted with baxdrostat.107 These early data suggest potentially more efficacious aldosterone suppression with limited off-target effects, warranting further clinical studies and direct head-to-head comparisons with established ASIs to fully validate the therapeutic utility of JX09 in PA and cardiovascular conditions.

Future Directions

ASIs represent a promising therapeutic advancement in mitigating the persistent challenges of excess aldosterone, including the phenomenon of ‘aldosterone escape’ and inadequate control of non-genomic pathways. Despite growing evidence of efficacy in lowering blood pressure and aldosterone levels, several critical gaps remain.

Most studies, to date, have focused on surrogate endpoints, such as reductions in blood pressure and aldosterone levels, leaving critical questions regarding long-term cardiovascular and kidney outcomes unanswered. Robust, large-scale Phase III trials evaluating endpoints such as heart failure hospitalisation, MI and CKD progression are essential to profile the full therapeutic potential of ASIs. Furthermore, subgroup analyses are needed to explore differential responses to ASIs in specific populations, including sex-based differences in MR pathways and patients with comorbidities such as diabetes, CKD or resistant hypertension. The integration of ASIs into current treatment paradigms also presents challenges that require further investigation. As add-on therapies, ASIs must demonstrate incremental benefits over existing RAAS inhibitors and MRAs. Synergistic effects, such as combining ASIs with SGLT2 inhibitors, should be explored to optimise outcomes in heart failure and CKD.

The future of ASIs lies in advancing therapeutic strategies and leveraging precision medicine. Dual-action inhibitors targeting aldosterone synthesis alongside pathways involved in inflammation or fibrosis hold promise for expanding the scope of treatment. Biomarker-guided approaches, such as the use of aldosterone–to–renin ratio or steroid metabolites, could refine patient selection and improve treatment efficacy. Additionally, novel approaches beyond small-molecule inhibition are emerging. MicroRNA-based strategies, such as modulation of microRNA-24, have been shown to post-transcriptionally regulate CYP11B2 and suppress aldosterone production.108 Incorporating such gene-silencing technologies could overcome some of the current challenges associated with ASIs, including off-target effects and variable selectivity.

Innovations in ASI formulations, including modified-release preparations, aim to optimise efficacy, adherence and safety profiles. Additionally, determining the non-genomic effects of aldosterone, such as oxidative stress and fibrosis, and assessing their modulation by ASIs could expand our understanding of their mechanisms of action and therapeutic potential. By addressing these gaps in clinical evidence and focusing on innovative, precision-driven approaches, ASIs have the potential to redefine the management of aldosterone-driven conditions and significantly improve patient outcomes.

Conclusion

ASIs are a groundbreaking advancement in aldosterone-targeted therapies, offering comprehensive suppression of both genomic and non-genomic effects while reducing the risks of hyperkalaemia and aldosterone escape seen with MRAs. Clinical trials have demonstrated that ASIs exhibit promising efficacy in reducing aldosterone levels and blood pressure with improved safety profiles, though long-term outcomes remain under investigation. With on-going research, ASIs have the potential to transform cardiovascular and kidney care and may help narrow critical gaps in current treatment paradigms.

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