balcinrenone (AZD9977) / AstraZeneca - LARVOL DELTA

Design and baseline characteristics of MIRO-CKD: a Phase IIb, Randomised, Double-Blind Clinical Trial to Evaluate Effects of Balcinrenone in Combination with Dapagliflozin vs. Dapagliflozin in Patients with CKD (ERA 2025) - P2 | " MIRO-CKD is a phase IIb, international, randomised, double-blind, parallel-group trial in adults with CKD (estimated glomerular filtration rate [eGFR] ≥25 to 100 to ≤5000 mg/g) and potassium ≥3.5 to ≤5mmol/L (NCT06350123), where participants have been randomised 1:1:1 to three treatment arms: balcinrenone/dapagliflozin 15 mg/10 mg, balcinrenone/dapagliflozin 40 mg/10 mg or placebo/dapagliflozin 10 mg for 12 weeks followed by an 8-week wash-out period to assess off-drug effects. MIRO-CKD is a fully recruited global phase IIb trial enrolling a contemporary CKD population at increased risk of disease progression and with an increased risk of hyperkalaemia based on their reduced kidney function. The study will assess the efficacy, safety and tolerability of the combination of balcinrenone and dapagliflozin with the aim to identify an optimal dose for a future phase III study in patients with CKD."

Clinical • Combination therapy • P2b data • Cardiovascular • Chronic Kidney Disease • Diabetes • Diabetic Nephropathy • Metabolic Disorders • Nephrology • Type 2 Diabetes Mellitus

A Study to Investigate the Effect of Food on Balcinrenone/Dapagliflozin Pharmacokinetics in Fed and Fasted State and Pharmacokinetics of Balcinrenone When Dosed With a P-gp Inhibitor in Healthy Participants. (clinicaltrials.gov) - P1 | N=14 | Not yet recruiting | Sponsor: AstraZeneca

New P1 trial

MIRO-CKD: Efficacy, Safety and Tolerability of Balcinrenone/Dapagliflozin Compared to Dapagliflozin in Adults With Chronic Kidney Disease (clinicaltrials.gov) - P2 | N=324 | Completed | Sponsor: AstraZeneca | Active, not recruiting ➔ Completed

Trial completion • Chronic Kidney Disease • Nephrology • Renal Disease

The effect of severe renal impairment on the pharmacokinetics, safety and tolerability of balcinrenone. (PubMed, Br J Clin Pharmacol) - P2, P3 | "Balcinrenone exposure was approximately two-fold higher in participants with severe renal impairment compared with the group-matched control participants. Based on linear regression analysis of total apparent balcinrenone clearance vs. baseline eGFR, the AUC exposure is predicted to be <50% higher in patients with an eGFR of 20 mL/min/1.73 m2 compared with those with an eGFR of 60 mL/min/1.73 m2. In light of these findings, no dose adjustment based on eGFR is needed in two ongoing studies that target these patients (MIRO-CKD [NCT06350123] and BalanceD-HF [NCT06307652])."

Journal • PK/PD data • Cardiovascular • Chronic Kidney Disease • Congestive Heart Failure • Heart Failure • Nephrology • Renal Disease

BalanceD-HF: Phase III study to evaluate the effect of balcinrenone/dapagliflozin in patients with heart failure and impaired kidney function (ChiCTR) - P3 | N=4800 | Sponsor: Peking Union Medical College Hospital; Peking Union Medical College Hospital

New P3 trial • Cardiovascular • Congestive Heart Failure • Heart Failure

A Phase I PK Study of Balcinrenone/Dapagliflozin in Healthy Chinese Participants (clinicaltrials.gov) - P1 | N=10 | Completed | Sponsor: AstraZeneca | Not yet recruiting ➔ Completed | Trial completion date: Apr 2025 ➔ Oct 2024 | Trial primary completion date: Apr 2025 ➔ Oct 2024

Trial completion • Trial completion date • Trial primary completion date

MIRO-CKD: Efficacy, Safety and Tolerability of Balcinrenone/Dapagliflozin Compared to Dapagliflozin in Adults With Chronic Kidney Disease (clinicaltrials.gov) - P2 | N=324 | Active, not recruiting | Sponsor: AstraZeneca | Recruiting ➔ Active, not recruiting | Trial completion date: Jan 2026 ➔ May 2025 | Trial primary completion date: Jan 2026 ➔ May 2025

Enrollment closed • Trial completion date • Trial primary completion date • Chronic Kidney Disease • Nephrology • Renal Disease

Balcinrenone/dapagliflozin in patients with heart failure and impaired kidney function – the Phase 3 BalanceD-HF study design (NCT06307652) (CVCT USA 2024) - P3 | No abstract available

Clinical • P3 data • Cardiovascular • Congestive Heart Failure • Heart Failure

MIRACLE: Efficacy, Safety and Tolerability of AZD9977 and Dapagliflozin in Participants With Heart Failure and Chronic Kidney Disease (clinicaltrials.gov) - P2 | N=153 | Completed | Sponsor: AstraZeneca | Phase classification: P2b ➔ P2

Phase classification • Cardiovascular • Chronic Kidney Disease • Congestive Heart Failure • Heart Failure • Nephrology • Renal Disease • NPPB

Concentration-QT modeling demonstrates that the selective mineralocorticoid receptor modulator, balcinrenone (AZD9977), does not prolong QT interval. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "Balcinrenone (AZD9977) is a selective mineralocorticoid receptor modulator in development in combination with dapagliflozin for treatment of heart failure with impaired kidney function and chronic kidney disease. Furthermore, the upper 90% ΔΔQTcF CI was estimated to be below the threshold of regulatory concern of 10 ms at all observed concentrations (up to 16.7 μmol/L). Hence, it can be concluded that balcinrenone does not induce QTcF prolongation at the high clinical exposure scenario."

Journal • Cardiovascular • Chronic Kidney Disease • Congestive Heart Failure • Heart Failure • Nephrology • Renal Disease

Study to Investigate the Effect of Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of Balcinrenone (clinicaltrials.gov) - P1 | N=30 | Completed | Sponsor: AstraZeneca | Recruiting ➔ Completed

Trial completion • Hepatology

A Phase IIb, Multicentre, Randomised, Double-Blind, Dose-finding Study to Evaluate the Efficacy, Safety and Tolerability of Balcinrenone in Combination with Dapagliflozin Compared with Dapagliflozin in Patients with Chronic Kidney Disease and Albuminuria (ChiCTR) - P2 | N=300 | Not yet recruiting | Sponsor: Zhongshan Hospital, Fudan University; Zhongshan Hospital, Fudan University

Combination therapy • New P2 trial • Chronic Kidney Disease • Nephrology • Renal Disease

A Phase 2b Dose-Finding Study to Evaluate Effects of Balcinrenone/Dapagliflozin vs. Dapagliflozin in Patients with CKD and Albuminuria (KIDNEY WEEK 2024) - P2, P2b | "Funding. Commercial Support – AstraZeneca ."

Clinical • P2b data • Cardiovascular • Chronic Kidney Disease • Congestive Heart Failure • Heart Failure • Hypotension • Nephrology • Renal Disease

A Phase I PK Study of Balcinrenone/Dapagliflozin in Healthy Chinese Participants (clinicaltrials.gov) - P1 | N=10 | Not yet recruiting | Sponsor: AstraZeneca

New P1 trial

Design Of BalanceD-HF - A Phase 3 Study To Evaluate The Effect Of Balcinrenone/Dapagliflozin In Patients With Heart Failure And Impaired Kidney Function (NCT06307652) (HFSA 2024) - P3 | "An independent Data Monitoring Committee is monitoring safety data on a regular basis. BalanceD-HF is a unique trial that is evaluating a novel MR modulator (balcinrenone) combined with an SGLT2i (dapagliflozin) in the understudied population of patients with HF (across the LVEF spectrum) and impaired kidney function."

Clinical • P3 data • Atrial Fibrillation • Cardiovascular • Congestive Heart Failure • Heart Failure • Nephrology • Renal Disease

Mineralocorticoid receptor (MR) antagonist eplerenone and MR modulator balcinrenone prevent renal extracellular matrix remodeling and inflammation via the MR/proteoglycan/TLR4 pathway. (PubMed, Clin Sci (Lond)) - "We identified a novel mechanism linking MR activation to the renal proteoglycan deposition and inflammation via the TLR4 pathway activation. Balcinrenone and eplerenone similarly blunted this pathway activation."

Journal • Cardiovascular • Chronic Kidney Disease • Fibrosis • Immunology • Inflammation • Nephrology • Renal Disease

Can the novel aldosterone inhibiting drug balcinrenone reduce hyperkalaemia and worsening renal function compared to steroidal mineralocorticoid receptor antagonists in heart failure? (PubMed, Eur J Heart Fail) - No abstract available

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure

Balcinrenone plus dapagliflozin in patients with heart failure and chronic kidney disease: Results from the phase 2b MIRACLE trial. (PubMed, Eur J Heart Fail) - "While the smaller than planned sample size limits interpretation, we did not see significant reduction in UACR in patients treated with balcinrenone plus dapagliflozin compared with dapagliflozin plus placebo."

Journal • P2b data • Cardiovascular • Chronic Kidney Disease • Congestive Heart Failure • Heart Failure • Nephrology • Renal Disease

A phase 2b, randomised, double-blind, active controlled, multi centre study to evaluate the efficacy, safety and tolerability of oral AZD9977 and dapagliflozin treatment in patients with heart failure (HEART FAILURE 2024) - No abstract available

Clinical • Late-breaking abstract • P2b data • Cardiovascular • Congestive Heart Failure • Heart Failure

Renal effects and safety between Asian and non-Asian chronic kidney disease and type 2 diabetes treated with nonsteroidal mineralocorticoid antagonists. (PubMed, J Diabetes) - "Nonsteroidal MRAs exhibited significant renal benefits by decreasing UACR and lowering SBP in Asian than that of non-Asian patients with CKD and T2DM, without increase of adverse events except hyperkalemia and eGFR decrease ≥30%."

Clinical • Journal • Cardiovascular • Chronic Kidney Disease • Diabetes • Hypertension • Metabolic Disorders • Nephrology • Renal Disease • Type 2 Diabetes Mellitus

MIRO-CKD: Efficacy, Safety and Tolerability of Balcinrenone/Dapagliflozin Compared to Dapagliflozin in Adults With Chronic Kidney Disease. (clinicaltrials.gov) - P2 | N=300 | Recruiting | Sponsor: AstraZeneca | Not yet recruiting ➔ Recruiting

Combination therapy • Enrollment open • Chronic Kidney Disease • Nephrology • Renal Disease

Study to Investigate the Effect of Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of Balcinrenone (clinicaltrials.gov) - P1 | N=28 | Recruiting | Sponsor: AstraZeneca | Not yet recruiting ➔ Recruiting

Enrollment open • Hepatology

BalanceD-HF: Study to Evaluate the Effect of Balcinrenone/Dapagliflozin in Patients With Heart Failure and Impaired Kidney Function (clinicaltrials.gov) - P3 | N=4800 | Recruiting | Sponsor: AstraZeneca | Not yet recruiting ➔ Recruiting

Enrollment open • Cardiovascular • Congestive Heart Failure • Heart Failure

Study to Investigate the Effect of Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of Balcinrenone (clinicaltrials.gov) - P1 | N=28 | Not yet recruiting | Sponsor: AstraZeneca

New P1 trial • Hepatology

MIRO-CKD: Efficacy, Safety and Tolerability of Balcinrenone/Dapagliflozin Compared to Dapagliflozin in Adults With Chronic Kidney Disease. (clinicaltrials.gov) - P2 | N=300 | Not yet recruiting | Sponsor: AstraZeneca

Combination therapy • New P2 trial • Chronic Kidney Disease • Nephrology • Renal Disease