zibotentan/dapagliflozin / AstraZeneca - LARVOL DELTA

Zibotentan and Dapagliflozin Combination, EvAluated in Liver Cirrhosis (ZEAL Study) (clinicaltrials.gov) - P2 | N=205 | Active, not recruiting | Sponsor: AstraZeneca | Recruiting ➔ Active, not recruiting

Enrollment closed • Monotherapy • Cardiovascular • Fibrosis • Gastroenterology • Hepatology • Hypertension • Immunology • Liver Cirrhosis • Portal Hypertension

ZODIAC: A Study to Investigate the Effects of Zibotentan/Dapagliflozin Combination Compared to Dapagliflozin Alone in Adult Participants With Chronic Kidney Disease and High Proteinuria (clinicaltrials.gov) - P2 | N=224 | Recruiting | Sponsor: AstraZeneca | Not yet recruiting ➔ Recruiting

Enrollment open • Chronic Kidney Disease • Nephrology • Renal Disease

Effects of combined treatment with zibotentan and dapagliflozin compared to dapagliflozin alone in patients with diabetic and non-diabetic chronic kidney disease. (PubMed, Diabetes Obes Metab) - "Combination therapy with zibotentan and dapagliflozin demonstrated consistent efficacy and safety across CKD patients with and without type 2 diabetes."

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

ZODIAC: Zibotentan and Dapagliflozin in Patients With Type 2 Diabetes and Elevated Albuminuria (clinicaltrials.gov) - P2 | N=42 | Completed | Sponsor: University Medical Center Groningen | Enrolling by invitation ➔ Completed | Trial completion date: Sep 2024 ➔ Mar 2025 | Trial primary completion date: Apr 2024 ➔ Mar 2025

Trial completion • Trial completion date • Trial primary completion date • Chronic Kidney Disease • Diabetes • Metabolic Disorders • Nephrology • Renal Disease • Type 2 Diabetes Mellitus

ZODIAC: A Study to Investigate the Effects of Zibotentan/Dapagliflozin Combination Compared to Dapagliflozin Alone in Adult Participants With Chronic Kidney Disease and High Proteinuria (clinicaltrials.gov) - P2 | N=224 | Not yet recruiting | Sponsor: AstraZeneca

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

ZEAL UNLOCK: A Phase IIb Study to Evaluate the Safety of Zibotentan/Dapagliflozin in Participants With Cirrhosis-ZEAL-UNLOCK (clinicaltrials.gov) - P2 | N=73 | Completed | Sponsor: AstraZeneca | Active, not recruiting ➔ Completed

Monotherapy • Trial completion • Fibrosis • Gastroenterology • Hepatology • Immunology • Liver Cirrhosis

Authors' Reply: Effects of Zibotentan and Dapagliflozin on Fluid Retention in Patients with CKD: Need More Evidence. (PubMed, J Am Soc Nephrol) - No abstract available

Journal • Chronic Kidney Disease

Effects of Zibotentan and Dapagliflozin on Fluid Retention in Patients with CKD: Need More Evidence. (PubMed, J Am Soc Nephrol) - No abstract available

Journal • Chronic Kidney Disease

Zibotentan and Dapagliflozin Combination, EvAluated in Liver Cirrhosis (ZEAL Study) (clinicaltrials.gov) - P2 | N=195 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Apr 2025 ➔ Aug 2025 | Trial primary completion date: Jan 2025 ➔ May 2025

Monotherapy • Trial completion date • Trial primary completion date • Cardiovascular • Fibrosis • Gastroenterology • Hepatology • Hypertension • Immunology • Liver Cirrhosis • Portal Hypertension

ZEAL UNLOCK: A Phase IIb Study to Evaluate the Safety of Zibotentan/Dapagliflozin in Participants With Cirrhosis-ZEAL-UNLOCK (clinicaltrials.gov) - P2 | N=73 | Active, not recruiting | Sponsor: AstraZeneca | Recruiting ➔ Active, not recruiting

Enrollment closed • Monotherapy • Fibrosis • Gastroenterology • Hepatology • Immunology • Liver Cirrhosis

Effects of combining zibotentan and dapagliflozins on chronic kidney disease: an innovative frontier. (PubMed, Int Urol Nephrol) - No abstract available

Journal • Chronic Kidney Disease • Nephrology • Renal Disease

Study to Investigate Efficacy, Safety, and Tolerability of Zibotentan/Dapagliflozin Compared to Dapagliflozin in Participants With Chronic Kidney Disease and High Proteinuria (ZENITH High Proteinuria) (clinicaltrials.gov) - P3 | N=1760 | Active, not recruiting | Sponsor: AstraZeneca | Recruiting ➔ Active, not recruiting | Trial completion date: Jun 2027 ➔ Jan 2027 | Trial primary completion date: Jun 2027 ➔ Jan 2027

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

Effects of Zibotentan Alone and in Combination with Dapagliflozin on Fluid Retention in Patients with CKD (KIDNEY WEEK 2024) - "We used Cox proportional hazards regression to assess the association between zibotentan/dapagliflozin treatment, baseline characteristics, and fluid retention, as well as the relationship between zibotentan plasma exposure and fluid retention. After 3 weeks of treatment with zibotentan 0.25, 1.5 or 5 mg plus dapagliflozin 10 mg, changes in body weight, BNP, and hemoglobin were independently associated with changes in ECF. High doses of zibotentan increased the risk of fluid retention which could be reduced with lower doses and addition of dapagliflozin. This risk was more pronounced at lower eGFR which highlights the need for combined use of low zibotentan doses and dapagliflozin in advanced CKD."

Clinical • Combination therapy • Chronic Kidney Disease • Nephrology

REDUCTIONS IN THE NAFLD FIBROSIS SCORE FROM THE ZENITH-CKD TRIAL SUPPORT EXPLORATION OF ZIBOTENTAN DAPAGLIFLOZIN COMBINATION IN CIRRHOSIS (UEGW 2024) - "A reduction in NFS was observed in this small exploratory analysis of patients with CKD and high risk for advanced liver fibrosis across all three active arms of the study. These data support further exploration of the effects of zibotentan and dapagliflozin in patients with liver cirrhosis as part of the ongoing ZEAL part B study. Further data from both the CKD and liver study programs are awaited."

Late-breaking abstract • Chronic Kidney Disease • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Nephrology

Zibotentan and Dapagliflozin for the Treatment of CKD (ZENITH-CKD Trial) (clinicaltrials.gov) - P2 | N=542 | Completed | Sponsor: AstraZeneca | Phase classification: P2b ➔ P2

Phase classification • Chronic Kidney Disease • Nephrology • Renal Disease

Effects of Zibotentan Alone and in Combination with Dapagliflozin on Fluid Retention in Patients with CKD. (PubMed, J Am Soc Nephrol) - "High doses of zibotentan were associated with a higher risk of fluid retention, which was attenuated with lower doses and the addition of dapagliflozin."

Combination therapy • Journal • Chronic Kidney Disease • Nephrology • Renal Disease

From Plan to Pivot: How Model-Informed Drug Development Shaped the Dose Strategy of the Zibotentan/Dapagliflozin ZENITH Trials. (PubMed, Clin Pharmacol Ther) - "Dose-response modeling of efficacy and Kaplan-Meier analyses of tolerability identified a kidney-function-based low-dose strategy of 0.25 or 0.75 mg zibotentan (with 10 mg dapagliflozin) to balance benefit/risk in ZENITH High Proteinuria. The applied clinical pharmacology and MIDD principles enabled successful Phase IIb dose finding, rationalized and built confidence in the innovative Phase III dosing strategy and identified a potential therapeutic window for zibotentan/dapagliflozin, providing the opportunity for a significant improvement in the treatment of chronic kidney disease with high proteinuria."

Journal • Chronic Kidney Disease • Nephrology • Renal Disease

Cardiometabolic benefits of low dose zibotentan and dapagliflozin 10mg in the ZENITH-CKD study (ERA-EDTA 2024) - P2b | "In the ZENITH-CKD study zibotentan used at low dose combined with dapagliflozin had incremental effects versus dapagliflozin alone on a range of cardiometabolic risk markers including blood pressure, LDL cholesterol, HbA1c and uric acid, without a significant increase in fluid retention."

Atrial Fibrillation • Cardiovascular • Chronic Kidney Disease • Nephrology

Dosing low, winning high: Unlocking the promise of endothelin antagonism for the treatment of CKD in the zibotentan/dapagliflozin ZENITH trials (ERA-EDTA 2024) - "The favourable benefit/risk profile that was demonstrated for combined zibotentan/dapagliflozin in ZENITH-CKD was enabled by the zibotentan low-dose strategy. The wide dose ranging and MIDD further enabled selection of a kidney-function based zibotentan dosing strategy for ZENITH High Proteinuria which is designed to further balance benefit/risk. The low-dose zibotentan strategy and the combination with dapagliflozin opened for the first time a therapeutic window for ET AR antagonists, with the potential to redefine their value for the treatment of CKD."

Cardiovascular • Chronic Kidney Disease • Congestive Heart Failure • Diabetes • Diabetic Nephropathy • Genito-urinary Cancer • Heart Failure • Metabolic Disorders • Nephrology • Oncology • Prostate Cancer • Solid Tumor • Type 2 Diabetes Mellitus

Effects of zibotentan and dapagliflozin on patients with compensated cirrhosis: a randomized double-blind placebo controlled exploratory pilot study (EASL-ILC 2024) - "Six weeks of treatment with zibo/dapa was safe and well tolerated in compensated cirrhosis. Fluid retention events were fewer than described in previous ERA trials. A reduction in HVPG was not observed, possibly reflecting a low number of patients with severe PH."

Clinical • Cardiovascular • Cholestasis • Diabetes • Fibrosis • Hepatology • Hypotension • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Pain • Portal Hypertension • Type 2 Diabetes Mellitus • EDN1

SGLT2i in CKD with high albuminuria: an observational real-world study (ERA-EDTA 2024) - P3 | "Patients with prior use of SGLT2i, immunosuppressive drugs, hydroxychloroquine, CKD stage 5 (based on eGFR <15 mL/min/1.73 m2 or dialysis), polycystic kidney disease, or type 1 or gestational diabetes were excluded. While treatment with RASi and SGLT2i are associated with reduced risk of renal outcomes in patients with CKD, awareness and management of residual albuminuria remains an area of unmet clinical need. The novel combination of zibotentan/dapagliflozin currently under investigation in the ZENITH High Proteinuria phase III trial (NCT06087835) seeks to address this need."

Clinical • Real-world • Real-world evidence • Cardiovascular • Chronic Kidney Disease • Congestive Heart Failure • Diabetes • Diabetic Nephropathy • Genetic Disorders • Gestational Diabetes • Heart Failure • Metabolic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease • Type 2 Diabetes Mellitus

Efficacy and safety of zibotentan in combination with dapagliflozin in patients with CKD according to baseline diabetes status and kidney function (ISN-WCN 2024) - P2b | "ZENITH-CKD confirmed 0.25 mg/10 mg zibotentan/dapagliflozin was highly effective in reducing albuminuria and was well tolerated irrespective of baseline diabetes status or kidney function."

Clinical • Combination therapy • Atrial Fibrillation • Cardiovascular • Chronic Kidney Disease • Diabetes • Diabetic Nephropathy • Metabolic Disorders • Nephrology • Renal Disease • Type 2 Diabetes Mellitus

ZEAL UNLOCK: A Phase IIb Study to Evaluate the Safety of Zibotentan/Dapagliflozin in Participants With Cirrhosis-ZEAL-UNLOCK (clinicaltrials.gov) - P2 | N=66 | Recruiting | Sponsor: AstraZeneca | Not yet recruiting ➔ Recruiting

Enrollment open • Monotherapy • Fibrosis • Gastroenterology • Hepatology • Immunology • Liver Cirrhosis

ZEAL UNLOCK: A Phase IIb Study to Evaluate the Safety of Zibotentan/Dapagliflozin in Participants With Cirrhosis-ZEAL-UNLOCK (clinicaltrials.gov) - P2 | N=66 | Not yet recruiting | Sponsor: AstraZeneca

New P2 trial • Fibrosis • Gastroenterology • Hepatology • Immunology • Liver Cirrhosis