Aldosterone Synthase Inhibitors Research Articles

Aldosterone synthase inhibitors for cardiorenal protection: ready for prime time?

Background: Aldosterone, through its genomic and non-genomic effects, plays an important role in cardiovascular and renal injury. Steroidal mineralocorticoid receptor antagonists (MRAs) are fundamental to offset the aldosterone-mediated cardiorenal damage, but side effects may limit their use in a substantial proportion of patients. On the other hand, non-steroidal mineralocorticoid receptor antagonists (NS-MRA) showed improved selectivity and safety profile. However, interfering with the MRA could only partially inhibit aldosterone mediated effect both because of escaping mechanisms and potential non-genomic activity. Summary: Inhibiting aldosterone synthesis could be a promising strategy to abolish aldosterone-mediated cardiovascular side effects. Aldosterone is primarily synthesized by the CYP11B2 enzyme, which is very similar to CYP11B1, a key enzyme involved in glucocorticoid production. Lack of specificity for CYP11B2 and consequent off-target effects hampered the development of first-generation aldosterone synthase inhibitors (ASIs). The subsequent development of highly specific ASIs led to successful clinical trials in patients with resistant and uncontrolled hypertension. Key Messages: A recent randomized clinical trial showed a significant benefit of ASIs in patients with chronic kidney disease and albuminuria. However, further outcome based clinical trials are needed to confirm the promising role of ASIs in cardiorenal damage.

Evidence for Aldosterone Antagonism in Heart Failure

Activation of the renin–angiotensin–aldosterone system is the ultimate pathophysiological hallmark in heart failure. Though aldosterone primarily appears to regulate electrolyte homeostasis by acting on distal nephrons in the kidneys, its effects are far-reaching across the cardiovascular system as its receptors are also expressed in vascular smooth muscle cells, endothelial cells, macrophages and cardiomyocytes. Aldosterone excess leads to vascular stiffness, vasoconstriction, endothelial dysfunction, inflammation, oxidative stress, cardiac fibrosis and hypertrophy, atherogenesis and thrombosis. Hence, aldosterone antagonism is an attractive proposition for heart failure management. The first-generation non-selective mineralocorticoid receptor antagonist spironolactone produced a spectacular reduction of cardiovascular outcomes in the seminal RALES study, while the selective second-generation congener eplerenone boasts two positive studies: EPHESUS and EMPHASIS-HF. The TOPCAT trial indicated that a specific subgroup of patients with heart failure with preserved ejection fraction may benefit from targeted therapy of mineralocorticoid receptor antagonists. Newer-generation non-steroidal mineralocorticoid antagonists and aldosterone synthase inhibitors are being evaluated in randomised trials.

The potential for improving cardio-renal outcomes in chronic kidney disease with the aldosterone synthase inhibitor vicadrostat (BI 690517): a rationale for the EASi-KIDNEY trial.

Patients with chronic kidney disease (CKD) are at risk of progressive loss of kidney function, heart failure, and cardiovascular death despite current proven therapies, including renin-angiotensin system inhibitors (RASi), sodium glucose co-transporter-2 inhibitors (SGLT2i), and statin-based regimens. RASi and SGLT2i reduce risk of CKD progression irrespective of primary cause of kidney disease, suggesting they target final common pathways. Targeting aldosterone overactivity with a nonsteroidal mineralocorticoid receptor antagonist (MRA) also reduces cardiorenal risk in patients with albuminuric diabetic kidney disease already treated with RASi. Together, these observations provide the rationale for trials to assess effects of inhibiting the aldosterone pathway in a broader range of patients with CKD, including those with non-diabetic causes of CKD or low albuminuria. Aldosterone synthase inhibitors (ASi) have emerged as an alternative to MRAs for aldosterone pathway inhibition. Phase II data from 586 patients with albuminuric CKD have shown that 10 mg of an ASi, vicadrostat (BI 690517), reduced urine albumin-to-creatinine ratio by ∼40% compared to placebo with or without concurrent empagliflozin treatment. MRA and ASi increase risk of hyperkalaemia. Combining their use with an SGLT2i may mitigate some of this risk, improving tolerability, and allowing a wider range of patients to be treated (including those with higher levels of blood potassium than in previous trials). The EASi-KIDNEY (NCT06531824) double-blind placebo-controlled trial will test this approach by assessing the safety and cardiorenal efficacy of vicadrostat in combination with empagliflozin in ∼11,000 patients with CKD. It will be sufficiently large to assess effects in patients with and without diabetes separately.

Systolic plood pressure response to ASi BI 690517 with and without empagliflozin in CKD

Abstract Background and Aims: BI 690517 is a highly selective aldosterone synthase inhibitor (ASi) in clinical development for CKD treatment. Coadministration of BI 690517 with a sodium-glucose cotransporter-2 inhibitor may provide additive efficacy and also mitigate risk of hyperkalaemia. This multinational, randomised, dose-finding, Phase II trial (NCT05182840) investigated the efficacy and safety of BI 690517, given alone or in combination with empagliflozin (EMPA), for albuminuria reduction in people with CKD and with or without type 2 diabetes.1 Here, we present a secondary analysis for effects on systolic blood pressure (SBP). Method Adults with CKD receiving a maximally tolerated dose of a renin-angiotensin system inhibitor were randomised (R1) 1:1 to receive background EMPA 10 mg or placebo (PBO-EMPA) during an 8-week run-in. They were then re-randomised (R2) 1:1:1:1 to receive BI 690517 (3 mg, 10 mg, or 20 mg) or PBO-ASI for 14 weeks, in addition to their assigned EMPA or PBO-EMPA therapy. Participants had mean baseline SBP ≥110 and ≤160 mmHg. Elevated blood pressure (BP) was defined as SBP ≥140 mmHg or DBP ≥90 mmHg and receiving ≥2 classes of anti-HTN medication. Changes in SBP from R2 baseline to Week 14 were analysed to assess BI 690517 effects with and without EMPA use. Results Of 714 people randomised at R1, 586 were randomised at R2, and the treated set consisted of 583 people. Demographics and clinical characteristics were similar between dose groups.1 At R2 baseline, 169 (29.0%) people had elevated BP. Mean SBP was 142.7 mmHg in the elevated BP group versus 129.2 mmHg in the non-elevated BP group. Treatment with BI 690517 consistently reduced SBP with reductions that were comparable in people with and without elevated BP (p-value for interaction not significant) (Table). Conclusions In people with CKD, BI 690517 reduced SBP in people with and without elevated BP.(Table)

Cumulative Effects of Aldosterone Synthase and SGLT2 Inhibition on Albuminuria in People with CKD

Cumulative Effects of Aldosterone Synthase and SGLT2 Inhibition on Albuminuria in People with CKD

The renin-angiotensin-aldosterone system: An old tree sprouts new shoots

The intricate physiological and pathological diversity of the Renin-Angiotensin-Aldosterone System (RAAS) underpins its role in maintaining bodily equilibrium. This paper delves into the classical axis (Renin-ACE-Ang II-AT1R axis), the protective arm (ACE2-Ang (1–7)-MasR axis), the prorenin-PRR-MAP kinases ERK1/2 axis, and the Ang IV-AT4R-IRAP cascade of RAAS, examining their functions in both physiological and pathological states. The dysregulation or hyperactivation of RAAS is intricately linked to numerous diseases, including cardiovascular disease (CVD), renal damage, metabolic disease, eye disease, Gastrointestinal disease, nervous system and reproductive system diseases. This paper explores the pathological mechanisms of RAAS in detail, highlighting its significant role in disease progression. Currently, in addition to traditional drugs like ACEI, ARB, and MRA, several novel therapeutics have emerged, such as angiotensin receptor-enkephalinase inhibitors, nonsteroidal mineralocorticoid receptor antagonists, aldosterone synthase inhibitors, aminopeptidase A inhibitors, and angiotensinogen inhibitors. These have shown potential efficacy and application prospects in various clinical trials for related diseases. Through an in-depth analysis of RAAS, this paper aims to provide crucial insights into its complex physiological and pathological mechanisms and offer valuable guidance for developing new therapeutic approaches. This comprehensive discussion is expected to advance the RAAS research field and provide innovative ideas and directions for future clinical treatment strategies.

Abstract P301: A Meta-Analysis of Randomized Controlled Trials: Aldosterone Synthase Inhibitors as a Therapeutic Strategy for Hypertension

Introduction: Hypertension is a widespread health concern globally, often associated with excessive aldosterone production. Aldosterone synthase inhibitors (ASIs) have been proposed as potential therapeutic agents. Yet, their effectiveness and safety in managing blood pressure in hypertensive adults are not definitively established. This study aims to elucidate this matter through a comprehensive systematic review and meta-analysis of Randomized Controlled Trials (RCTs). Hypothesis: We hypothesize that ASIs could be a safe and effective strategy for managing blood pressure in adults diagnosed with hypertension. Methods: A systematic review and meta-analysis of seven RCTs were conducted to assess the impact of ASIs versus placebo in hypertensive patients. The studies were systematically sourced from MEDLINE and EMBASE until March 30 th , 2024. Continuous outcomes were pooled using the mean difference (MD), and dichotomous outcomes were pooled using the risk ratio (RR), both with their respective confidence intervals (CI). Results: Our meta-analysis incorporated data from seven randomized studies, averaging 7.7 ± 2.4 weeks in duration, and involving a total of 1440 patients. Compared to placebo, ASIs showed effectiveness in controlling systolic blood pressure (MD: -6.12 mm Hg; 95% CI [−4.32, −7.92]; p < 0.0001; I 2 = 0%) and diastolic blood pressure (MD: −2.71; 95% CI [−1.07, −4.36]; p = 0.001; I 2 = 0%). Notably, the incidence of adverse events did not significantly differ from that observed with placebo (RR: 1.11; 95% CI 0.95 to 1.29; p = 0.18; I 2 = 0%). Conclusions: Our findings suggest that ASIs could be a safe and effective approach for managing blood pressure in hypertensive adults, with no significant difference in the incidence of adverse events compared to placebo. These results advocate for further investigation of ASIs in larger, long-term trials to confirm their safety and efficacy, and to explore any additional therapeutic benefits over mineralocorticoid receptor antagonists. Future research should also thoroughly examine the potential benefits of these inhibitors in diverse patient populations, including those with obesity-associated hypertension and suppressed plasma renin activity.

Abstract P440: Discovery of clinical candidate GSC002219, a highly selective oral CYP11B2 inhibitor for hypertension

Background: Aldosterone is an important mediator of hypertension and its aberration could contribute to heart and kidney diseases. Aldosterone synthase inhibitors (ASI) attenuate the production of aldosterone directly and have been proposed as an alternative to mineralocorticoid receptor antagonists (MRA) for treatment of resistant hypertension and chronic renal disease. GSC002219 is a potent inhibitor of aldosterone synthase (CYP11B2) with high selectivity over the closely related enzyme CYP11B1. The aim of the study was to evaluate the effect of GSC002219 on aldosterone and blood pressure. Methods: The inhibitory effect of GSC002219 against CYP11B2 and CYP11B1 proteins was assessed in human renal leiomyoblastoma cells expressing recombinant human / cynomolgus CYP11B1or CYP11B2 enzymes, respectively. GSC002219 was further evaluated in Synacthen (ACTH) challenged cynomolgus monkey model for its effects against various related key biomarkers including cortisol, aldosterone and precursors. The effects of GSC002219 on systolic blood pressure (SBP) and diastolic blood pressure (DBP) were evaluated in stroke-prone spontaneously hypertensive rat (SHRSP) model. Results: GSC002219 potently inhibits CYP11B2 with an IC 50 of 27nM, while maintains a >150-fold selectivity over CYP11B1. In ACTH challenged cynomolgus monkey model, single oral doses of GSC002219 at 0.03 mg/kg and 0.1 mg/kg could suppress aldosterone production to 80% and 93%, respectively, comparing to vehicle-treated animals without any effect towards cortisol levels. In the rat SHRSP hypertension model, GSC002219 could effectively lower both SBP and DBP. GSC002219 has an excellent in vitro ADME and toxicology profile as well as a balanced physicochemical property. In 14-day rat and monkey toxicology studies, GSC002219 displayed good tolerance, excellent PK profile and a great safety window (>100 fold). Conclusions: Taken together, GSC002219 is a safe and potent inhibitor of CYP11B2 and efficacious in various disease models of hypertension. GSC002219 is under IND-enabling study and may enter the clinical development early 2025.

First-in-human study evaluating safety, pharmacokinetics, and pharmacodynamics of lorundrostat, a novel and highly selective aldosterone synthase inhibitor.

Dysregulation of the mineralocorticoid hormone aldosterone is an increasingly prevalent cause of hypertension. Aldosterone synthase (CYP11B2) shares 93% homology to 11β-hydroxylase (CYP11B1), which produces cortisol. Lorundrostat, a highly selective inhibitor of CYP11B2, is a potential safe and effective treatment for aldosterone-dependent, uncontrolled hypertension, including treatment-resistant hypertension. Lorundrostat showed highly selective inhibition of CYP11B2 invitro, with 374-fold selectivity for CYP11B2 vs. CYP11B1. A first-in-human study of single ascending doses ranging from 5 to 800 mg and multiple ascending doses ranging from 40 to 360 mg once daily was conducted in healthy participants. After single- and multiple-dose administration, lorundrostat plasma levels peaked 1-3 h after administration with a t1/2 of 10-12 h. Plasma aldosterone decreased up to 40% with single 100-mg to 200-mg doses and up to 70% with single 400 to 800-mg doses. Plasma aldosterone returned to baseline within 16 h after single 100-mg doses and multiple once-daily 120-mg doses. Lorundrostat demonstrated a favorable safety profile in healthy participants. Dose- and exposure-dependent inhibition of renal tubular sodium reabsorption was observed across a clinically relevant dose range with no suppression of basal or cosyntropin-stimulated cortisol production and only a modest increase in mean serum potassium.

New ways of mitigating aldosterone in cardiorenal disease.

Steroidal mineralocorticoid receptor antagonists (MRAs) bind to the mineralocorticoid receptor and antagonize the effects of aldosterone, which contributes to the development and progression of cardio- and renovascular diseases. Guidelines recommend steroidal MRAs in patients with heart failure with reduced or mildly reduced ejection fraction, as they reduce morbidity and mortality. In heart failure with preserved ejection fraction, MRAs have not convincingly shown to improve prognosis. Steroidal MRAs delay the progression of chronic kidney disease, reduce proteinuria and lower blood pressure in resistant hypertension but can induce hyperkalaemia. Due to their limited selectivity to the mineralocorticoid receptor, steroidal MRAs can cause significant adverse effects, i.e. libido loss, erectile dysfunction, gynaecomastia, and amenorrhoea, leading to low rates of persistance. Against this background, new avenues for developing non-steroidal, selective (ns)MRAs and aldosterone-synthase inhibitors have been taken. Finerenone has been shown to delay the progression of diabetic nephropathy and lower the incidence of heart failure hospitalizations in patients with chronic kidney disease and diabetes compared with placebo. Finerenone has therefore been recommended by the 2023 European Society of Cardiology Guidelines for the management of diabetes in patients with type 2 diabetes and chronic kidney disease. Further randomized controlled trials assessing the safety and effectiveness of finerenone in patients with heart failure are currently ongoing. Esaxerenone provides antihypertensive effects and has been approved for the treatment of hypertension in Japan. Baxdrostat and lorundostat, novel selective aldosterone-synthase inhibitors, are currently under investigation. In phase II trials, baxdrostat and lorundostat were safe and effective in lowering blood pressure in resistant hypertension. In this review, we summarize and critically discuss the evidence for new drugs mitigating aldosterone in heart failure, hypertension, and chronic kidney disease.

#1418 Phase II dose-selection, randomised, controlled trial of ASi BI 690517 with and without EMPA in CKD: subgroup analysis by T2D status

Abstract Background and Aims High aldosterone levels accelerate chronic kidney disease (CKD) progression. BI 690517 is a highly selective aldosterone synthase inhibitor (ASi) in clinical development for CKD treatment. ASi may reduce deleterious haemodynamic, inflammatory, and fibrotic actions of aldosterone. Coadministration of BI 690517 with a sodium-glucose cotransporter-2 inhibitor may also mitigate the risk of hyperkalaemia. This multinational, randomised, dose-finding, Phase II trial (NCT05182840) investigated the efficacy and safety of BI 690517, given either alone or in combination with empagliflozin (EMPA), in people who had CKD with or without type 2 diabetes (T2D) [1, 2]. Here, we present an analysis by T2D status (pooled for background randomizedon to EMPA or placebo [PBOEMPA]). Method Adults with CKD receiving a maximally tolerated dose of a renin-angiotensin system inhibitor were randomized (R1) 1:1 to an 8-week run-in to receive background EMPA 10 mg or PBOEMPA, then randomized again (R2) 1:1:1:1 to receive BI 690517 (3 mg, 10 mg, or 20 mg) or PBOASI for 14 weeks. The primary endpoint was the change from R2 baseline in urine albumin:creatinine ratio (UACR) in the first morning void of urine at Week 14. A secondary endpoint was UACR response (≥30% reduction from R2 baseline in UACR at Week 14). Changes in systolic blood pressure (SBP) and estimated glomerular filtration rate (eGFR) from R2 baseline to Week 14 were also assessed, as were safety outcomes. Results Of 586 people randomized at R2, 414 (70.6%) were reported to have T2D and 172 (29.4%) did not have T2D. Baseline demographics and clinical characteristics were mostly similar between these two groups [1]; however, those with T2D had higher mean BMI (30.6 vs 28.3 kg/m2), SBP (135.3 vs 130.2 mmHg) and eGFR (53.0 vs 49.4 mL/min/1.73 m2), and higher median UACR (444.7 vs 409.2 mg/g) than those without T2D. BI 690517 consistently reduced UACR versus PBOASI in people with and without T2D (p = 0.38, indicating no difference in treatment effect between these groups), with the largest reductions observed in the 10 mg and 20 mg dose groups; however, for the 3 mg dose group, UACR reduction was only observed in people with T2D (Figure). UACR response rates (≥30% reduction) were achieved in more than half of people with and without T2D in the BI 690517 10 mg and 20 mg dose groups, with the highest response rates in those also receiving EMPA (10 mg dose group: with T2D, 74.3%; without T2D, 64.0%). Decreases in SBP and small decreases in eGFR were also observed in people with and without T2D in response to BI 690517 10 mg and 20 mg, and were consistent with the observed changes in the overall population; however, for the 3 mg dose group, eGFR reduction was only observed in people with T2D. Adverse events leading to discontinuation in BI 690517 10 mg and 20 mg dose groups were more common among people with T2D than those without T2D who were receiving the same dose of BI 690517. Conclusion In people who had CKD, with or without T2D, BI 690517 dose-dependently reduced UACR, with high rates of UACR response suggestive of additive beneficial effects when given with EMPA.

Diuretic effects of Hecogenin and Hecogenin acetate via aldosterone synthase inhibition

Hecogenin (HEC) is a steroidal saponin found in many plant species and serves as a precursor for steroidal drugs. The diuretic effects of HEC and its derivative, hecogenin acetate (HA), remain largely unexplored. The present study aimed to explore the potential diuretic effects of HEC and HA compared to furosemide (FUR) and spironolactone (SPIR). Additionally, the study aimed to explore the underlying mechanism particularly focusing on aldosterone synthase gene expression. Fifty-four Sprague-Dawley rats were allocated into nine groups (Group 1–9). Group 1 (control) received the vehicle, Groups 2 received FUR 10 mg/kg, Group 3, 4, and 5 were given HEC, while Groups 6, 7 and 8 received HA i.p at doses of 5, 10, and 25 mg/kg, respectively. Group 9 received SPIR i.p at the dose of 25 mg/kg. Urine volume, diuretic index and diuretic activity were monitored at 1, 2, 3, 4, 5, 6, and 24 h post-administration. Treatment was given daily for seven days. After that, rats were sacrificed and blood was collected for serum electrolytes determination. Adrenal glands were dissected out for gene expression studies. The results revealed that HEC and HA at the administered doses significantly and dose-dependently increased urine and electrolyte excretion. These results were primarily observed at 25 mg/kg of each compound. Gene expression studies demonstrated a dose-dependent reduction in aldosterone synthase gene expression, suggesting aldosterone synthesis inhibition as a potential mechanism for their diuretic activity. Notably, HA exhibited more pronounced diuretic effects surpassing those of HEC. This enhanced diuretic activity of HA can be attributed to its stronger impact on aldosterone synthase inhibition. These findings offer valuable insights into the diuretic effects of both HEC and HA along with their underlying molecular mechanisms.

RATIONALE AND DESIGN OF PHASE 3 TRIAL FOR BAXDROSTAT, A NOVEL HIGHLY SELECTIVE ALDOSTERONE SYNTHETASE INHIBITOR

Objective: Aldosterone is a key driver of cardiorenal disease as well as hard-to-treat hypertension. Highly selective aldosterone synthase inhibitors (ASI) are a new class of anti-hypertensive therapy that hold great promise for management of blood pressure (BP), having demonstrated BP lowering in a proof-of-concept study. The rationale for and design of a phase 3 trial with the novel ASI baxdrostat are described here. Design and method: The international, multicenter, randomized, double-blind, placebo-controlled phase 3 BaxHTN trial (NCT06034743) will enroll approximately 720 adults with uncontrolled or resistant hypertension defined as seated office systolic BP greater than/equal to 135 mmHg despite 2+ antihypertensives including a diuretic, serum potassium 3.5-5.0 mmol/L, and eGFR greater than/equal to 45mL/min/1.73m2. Given the need to address long-term efficacy but limit placebo use due to the risks of uncontrolled hypertension, the study will have 4 sequential parts following placebo run-in: 1) 12-week double-blind period, 1:1:1 randomization to baxdrostat 2 mg, baxdrostat 1 mg, or placebo; 2) 12-week open label period, re-randomization of the placebo and 1 mg arms to 2 mg or standard-of-care; 3) 8-week randomized withdrawal period to 2 mg or placebo; and 4) 20-week open label period. The primary endpoint will be the change in office systolic BP from baseline to 12 weeks. Adverse events will be evaluated under independent data monitoring committee supervision. Results: Results are expected in late 2025. Conclusions: The phase 3 BaxHTN trial design will allow assessing the safety of baxdrostat and its effect on BP in patients with uncontrolled or resistant hypertension. Results are expected in late 2025.

Safety and efficacy of once-daily dexfadrostat phosphate in patients with primary aldosteronism: a randomised, parallel group, multicentre, phase 2 trial

Primary aldosteronism (PA) is caused by autonomous aldosterone overproduction and characterised by uncontrolled hypertension. There are currently no treatments that targetaldosterone synthesis. We evaluated the safety and efficacy of a novel aldosterone synthase inhibitor, dexfadrostat phosphate, in patients with PA. This multi-centre, randomised, phase 2 trial was conducted between November 2019 and May 2022 (NCT04007406; EudraCT code 2019-000919-85). Adults with PA and an office systolic blood pressure of 145-190mmHg were included. After a 2-week single-blind placebo run-in period, participants were randomised 1:1:1 to receive oral dexfadrostat phosphate 4, 8, or 12mg once daily for an 8-week double-blind treatment period, followed by a 2-week single-blind placebo withdrawal period. Randomisation was conducted centrally and stratified by centre and sex. At the beginning and end of the treatment period, 24h ambulatory systolic blood pressure (aSBP) was recorded. Blood samples were taken every 2 weeks. Primary endpoints were the change in aldosterone-to-renin ratio (ARR) and mean 24h aSBP from baseline to the end of the treatment period in the combined dose group of all participants receiving any dose of dexfadrostat phosphate. Safety endpoints were the occurrence of treatment-emergent adverse events (TEAEs) and serious adverse events over the entire study in all randomised participants who received at least one dose of dexfadrostat phosphate. In total, 35 participants received dexfadrostat phosphate and all participants completed the study. Twenty-six participants (74.3%) were male, the mean age was 51.9 years (SD 8.7), and most were White (n=32, 91.4%). The median ARR and the mean 24h aSBP significantly decreased from the beginning to the end of the treatment period in the combined dose group (ARR: 15.3 vs 0.6, least-squares mean [LSM] change in log-normal values-2.5, p<0.0001; aSBP: 142.6 vs 131.9mmHg, LSM change-10.7mmHg, p<0.0001). There were no safety concerns; all TEAEs were mild or moderate and there were no serious TEAEs. Dexfadrostat phosphate corrected the ARR and aSBP and was well tolerated in patients with PA, demonstrating the benefit of pharmacologically targeting the source of hyperaldosteronism. DAMIAN Pharma AG.

Lorundrostat may cause a clinically significant decline in renal function; a letter to the editor

Lorundrostat is an aldosterone synthase inhibitor that can be used in patients with uncontrolled hypertension. It effectively lowers blood pressure, but there are concerns about the limited renal safety data available for lorundrostat. In order to address this issue, it is recommended that future research should incorporate more detailed kidney assessments, which would include monitoring for conditions such as proteinuria and acute kidney injury (AKI). This paper discusses the effects of lorundrostat on the estimated glomerular filtration rate (eGFR) and highlights the significant variability in these effects among individuals. The research shows that lorundrostat may cause a decline in eGFR exceeding one standard deviation above the mean change in approximately 16% of patients. In severe cases, 0.2% of patients may experience eGFR declines of ≥42 mL/min/1.73 m². These declines in eGFR could increase chronic kidney disease (CKD) stages, even in those with baseline eGFR &gt;60 or 90 mL/min/1.73 m². In conclusion, while most lorundrostat patients do not experience severe eGFR declines, there is still a risk of clinically meaningful declines and CKD progression, particularly among susceptible individuals. Further research is needed to confirm these findings and identify renal risk factors in uncontrolled hypertension patients who receive aldosterone synthase inhibition.

Molecular Targets of Novel Therapeutics for Diabetic Kidney Disease: A New Era of Nephroprotection.

Diabetic kidney disease (DKD) is a chronic microvascular complication in patients with diabetes mellitus (DM) and the leading cause of end-stage kidney disease (ESKD). Although glomerulosclerosis, tubular injury and interstitial fibrosis are typical damages of DKD, the interplay of different processes (metabolic factors, oxidative stress, inflammatory pathway, fibrotic signaling, and hemodynamic mechanisms) appears to drive the onset and progression of DKD. A growing understanding of the pathogenetic mechanisms, and the development of new therapeutics, is opening the way for a new era of nephroprotection based on precision-medicine approaches. This review summarizes the therapeutic options linked to specific molecular mechanisms of DKD, including renin-angiotensin-aldosterone system blockers, SGLT2 inhibitors, mineralocorticoid receptor antagonists, glucagon-like peptide-1 receptor agonists, endothelin receptor antagonists, and aldosterone synthase inhibitors. In a new era of nephroprotection, these drugs, as pillars of personalized medicine, can improve renal outcomes and enhance the quality of life for individuals with DKD.

Aldosterone synthase inhibitor (BI 690517) therapy for people with diabetes and albuminuric chronic kidney disease: A multicentre, randomized, double-blind, placebo-controlled, Phase I trial.

This Phase I study evaluated the safety and early efficacy of an aldosterone synthase inhibitor (BI 690517) in people with diabetes and albuminuric chronic kidney disease. Double-blind, placebo-controlled study (NCT03165240) at 40 sites across Europe. Eligible participants [estimated glomerular filtration rate ≥20 and <75 ml/min/1.73 m2; urine albumin/creatinine ratio (UACR) ≥200 and <3500 mg/g] were randomized 6:1 to receive once-daily oral BI 690517 3, 10 or 40 mg, or eplerenone 25-50 mg, or placebo, for 28 days. The primary endpoint was the proportion of participants with drug-related adverse events (AEs). Secondary endpoints included changes from baseline in the UACR. Fifty-eight participants were randomized and treated from 27 November 2017 to 16 April 2020 (BI 690517: 3 mg, n = 18; 10 mg, n = 13; 40 mg, n = 14; eplerenone, n = 4; placebo, n = 9) for 28 days. Eight (13.8%) participants experienced drug-related AEs [BI 690517: 3 mg (two of 18); 10 mg (four of 13); 40 mg (two of 14)], most frequently constipation [10 mg (one of 13); 40 mg (one of 14)] and hyperkalaemia [3 mg (one of 18); 10 mg (one of 13)]. Most AEs were mild to moderate; one participant experienced severe hyperkalaemia (serum potassium 6.9 mmol/L; BI 690517 10 mg). UACR responses [≥20% decrease from baseline (first morning void urine) after 28 days] were observed for 80.0% receiving BI 690517 40 mg (eight of 10) versus 37.5% receiving placebo (three of eight). Aldosterone levels were suppressed by BI 690517, but not eplerenone or placebo. BI 690517 was generally well tolerated, reduced plasma aldosterone and may decrease albuminuria in participants with diabetes and albuminuric chronic kidney disease.

Revolutionising CKD Care: Novel Treatment Paradigms and Cutting-edge Strategies

Chronic Kidney Disease (CKD) represents a public health crisis globally. New therapeutic horizons in CKD management encompass a diverse array of options for a more holistic and personalised approach. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors exhibit promising results in preserving kidney function and mitigating cardiovascular risks in patients with or without diabetes. Non-steroidal selective Mineralocorticoid Receptor Antagonists (MRA) present targeted strategies for CKD management. Glucagon-like peptide-1 (GLP-1) receptor agonists offer innovative approaches for glycaemic control and complication reduction. Endothelin Receptor Antagonists contribute to CKD care by modulating endothelial function and reducing kidney damage. Aldosterone synthase inhibitors offer a unique angle, targeting aldosterone production to manage CKD-related complications. Additionally, hypoxia-inducible factor (HIF) inhibitors represent a cutting-edge therapeutic class, addressing the hypoxic conditions associated with kidney damage. This diverse range of advancements underscores a transformative shift towards more personalised and effective CKD treatments, providing newfound optimism for improved patient outcomes. Beyond providing evidence-based insights into recent therapeutic advancements in CKD, this review also delineates contemporary treatment guidelines for CKD. It underscores the imperative for holistic strategies to enhance outcomes for individuals grappling with this complex condition.

Use of Genomics to Develop Novel Therapeutics and Personalize Hypertension Therapy.

Hypertension is a prevalent public health problem, contributing to >10 million deaths annually. Though multiple therapeutics exist, many patients suffer from treatment-resistant hypertension or try several medications before achieving blood pressure control. Genomic advances offer mechanistic understanding of blood pressure variability, therapeutic targets, therapeutic response, and promise a stratified approach to treatment of primary hypertension. Cyclic guanosine monophosphate augmentation, aldosterone synthase inhibitors, and angiotensinogen blockade with silencing RNA and antisense therapies are among the promising novel approaches. Pharmacogenomic studies have also been done to explore the genetic bases underpinning interindividual variability in response to existing therapeutics. A polygenic approach using risk scores is likely to be the next frontier in stratifying responses to existing therapeutics.

Emerging Therapies for Treatment-Resistant Hypertension: A Review of Lorundrostat and Related Selective Aldosterone Synthase Inhibitors.

The target-hypertension (Target-HTN) trial investigated the efficacy and safety of lorundrostat, an aldosterone synthase inhibitor, as an antihypertensive. Cohort 1 of the trial includes patients with suppressed plasma renin activity and elevated aldosterone levels. Lorundrostat doses of 100 mg and 50 mg daily significantly decreased systolic blood pressure compared to the placebo group. Cohort 2 also demonstrated a reduction in systolic blood pressure with the 100 mg daily dose of lorundrostat. Lorundrostat is more selective for the inhibition of CYP11B2 versus CYP11B1, which makes it preferable to other aldosterone synthase inhibitors that inhibit cortisol synthesis, such as osilodrostat. Phase 3 trials are needed to validate the safety and efficacy of lorundrostat, and further research should be performed on other selective aldosterone synthase inhibitors such as baxdrostat, dexfadrostat, and BI 690517.