zibotentan (ZD4054) / AstraZeneca - LARVOL DELTA

Endothelin Receptor Antagonists in Resistant Hypertension and Proteinuric Kidney Disease: Receptor Strategy and Volume Management. (PubMed, J Clin Hypertens (Greenwich)) - "Aprocitentan is the first and only ERA approved for hypertension; in PRECISION, the approved 12.5-mg once-daily dose reduced placebo-corrected 24-h ambulatory systolic blood pressure by 4.2 mm Hg, with reductions of 4.2 to 5.9 mm Hg across the studied doses. In IgA nephropathy (IgAN), sparsentan reduces proteinuria and slows estimated glomerular filtration rate (eGFR) decline. Atrasentan has an established antiproteinuric effect and a favorable eGFR slope, although the prespecified week-136 eGFR contrast in the final ALIGN analysis did not reach statistical significance. Zibotentan plus dapagliflozin remains investigational. Across these settings, successful ERA use depends on careful patient selection, indication-specific interpretation of the evidence, optimized diuretic and cardiorenal therapy, and early surveillance for edema, anemia, liver-test abnormalities, and pregnancy risk, with treatment interruption or discontinuation when clinically significant..."

Journal • Review • Cardiovascular • Chronic Kidney Disease • Glomerulonephritis • Hematological Disorders • Hypertension • IgA Nephropathy • Nephrology • Pulmonary Arterial Hypertension • Pulmonary Disease • Renal Disease • Respiratory Diseases

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 | Active, not recruiting | Sponsor: AstraZeneca | Recruiting ➔ Active, not recruiting

Enrollment closed • Chronic Kidney Disease • Nephrology • Renal Disease

Design and baseline characteristics of the ZENITH high proteinuria trial testing zibotentan/dapagliflozin efficacy in CKD. (PubMed, Nephrol Dial Transplant) - P3 | "To evaluate the effect of zibotentan and dapagliflozin combination therapy, the ZENITH High Proteinuria study has successfully recruited a population at high risk of CKD progression for whom novel therapies remain necessary. Results are expected in 2027."

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

Next-generation therapeutics and renaissance of legacy drugs targeting the endothelin system. (PubMed, Can J Physiol Pharmacol) - "Endothelin-1 (ET-1) was discovered in 1988, followed by identification of ETA and ETB receptors in 1990, enabling rapid development of the first endothelin receptor antagonists (bosentan, ambrisentan, and macitentan) for pulmonary arterial hypertension, a condition marked by elevated ET-1. Nearly a decade later, a new therapeutic wave began with the ETB agonist sovateltide (2021) for cerebral ischemic stroke, demonstrating the benefits of ETB activation...Clazosentan (ETA) for cerebral vasospasm and aprocitentan (ETA/ETB) for resistant hypertension extended endothelin-targeted therapy into more common diseases. In kidney disease, sparsentan (AT1/ETA) and atrasentan (ETA) have both been approved for IgA nephropathy, with atrasentan succeeding after earlier failed trials...This review outlines approaches for identifying legacy endothelin compounds suitable for new indications, using zibotentan, now combined with dapagliflozin to reduce fluid retention as an example. Kidney..."

Journal • Review • Cardiovascular • Glomerulonephritis • Hypertension • IgA Nephropathy • Ischemic stroke • Nephrology • Pulmonary Arterial Hypertension • Pulmonary Disease • Renal Disease • Respiratory Diseases • EDN1

Improving the Cardiorenal Usability of Endothelin Receptor Antagonism in Albuminuric Chronic Kidney Disease: A Testable Role for SGLT2 Inhibitor-based Mitigation of Fluid Retention. (PubMed, Cardiovasc Drugs Ther) - "Combined ERA/SGLT2i therapy should be viewed as a mechanistically plausible and clinically testable positioning strategy, not an established treatment paradigm. Broader adoption requires confirmation of durable kidney benefit, cardiovascular safety, real-world feasibility, and reproducible tolerability across eGFR strata and congestion-prone CKD phenotypes."

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

Design and baseline characteristics of the ZENITH High Proteinuria trial: Zibotentan/dapagliflozin efficacy on chronic kidney disease progression (ERA 2026) - P2, P3 | "Image Table. Baseline characteristics"

Clinical • Cardiovascular • Chronic Kidney Disease • Congestive Heart Failure • Diabetes • Diabetic Nephropathy • Heart Failure • Metabolic Disorders • Nephrology • Renal Disease • Type 2 Diabetes Mellitus

Combined zibotentan/dapagliflozin shows a well-described and competitive clinical pharmacology profile, supporting broad usage in proteinuric CKD (ERA 2026) - No abstract available

Clinical • Chronic Kidney Disease • Renal Disease

A Study to Investigate the Concentrations of Zibotentan and Dapagliflozin in Blood When Given With and Without Food (clinicaltrials.gov) - P1 | N=26 | Completed | Sponsor: AstraZeneca | Recruiting ➔ Completed

Trial completion

IDENTIFYING A NOVEL SIGNALING MECHANISM FOR ENDOTHELIN-1-INDUCED CONSTRICTION OF CORONARY ARTERIOLES GUIDES DRUG DEVELOPMENT FOR THE CLASSIFICATION AND THERAPY OF CORONARY MICROVASCULAR DYSFUNCTION (ACC 2026) - P2, P3 | "L-type calcium channel blocker nifedipine (1 μM) prevented and reversed vasoconstriction to PDBu but not to ET-1. A clinical level of ET-1 caused profound and long-lasting narrowing of porcine coronary arterioles and was reversed by blockade of ROCK but not PKC, ETA receptors, or L-type calcium channels. Thus, the current data may explain why zibotentan or diltiazem failed to show clinical benefit for CMD. A new druggable target, i.e., ROCK, might be a solution for managing CMD."

Cardiovascular • Myocardial Ischemia • EDN1

A Study to Investigate the Concentrations of Zibotentan and Dapagliflozin in Blood When Given With and Without Food (clinicaltrials.gov) - P1 | N=26 | Recruiting | Sponsor: AstraZeneca | Not yet recruiting ➔ Recruiting

Enrollment open

Exercise treadmill testing for efficacy evaluation in randomized, controlled trials. (PubMed, Am Heart J) - P2 | "The Precision Medicine with Zibotentan in Microvascular Angina trial evaluated the selective endothelin-A receptor antagonist zibotentan as a potential disease-modifying therapy for microvascular angina...In conclusion, the exercise test has limitations as an objective endpoint of efficacy in randomized trials. PRIZE; https://clinicaltrials.gov/study/NCT04097314."

Clinical • Journal • Cardiovascular • Myocardial Ischemia

A Study to Investigate the Concentrations of Zibotentan and Dapagliflozin in Blood When Given With and Without Food (clinicaltrials.gov) - P1 | N=26 | Not yet recruiting | Sponsor: AstraZeneca

New P1 trial

Diabetes Mellitus and Chronic Kidney Disease: The Future Is Being Surpassed. (PubMed, J Clin Med) - "(5) The mineralocorticoid receptor antagonist (MRA) finerenone has been tested in RCTs as a kidney protective agent...Many novel agents-many of them proven not only for DM management but also for the treatment of obesity with or without DM or heart failure (HF)-are now in development and may be added to the five classical pillars: other non-steroidal MRA (balcinrenone); aldosterone synthase inhibitors (baxdrostat and vicadrostat); other GLP-1 RA (tirzepatide, survodutide, retatrutide, and cagrilintide); ET1 R antagonists, (zibotentan); and soluble guanylate cyclase activators (avenciguat). These new agents aim to slow disease progression further and reduce cardiovascular risk. Future strategies rely on integrated, patient-centered approaches and personalized therapy to curb renal disease and its related complications."

Journal • Review • Cardiovascular • Chronic Kidney Disease • Congestive Heart Failure • Diabetes • Diabetic Nephropathy • Genetic Disorders • Heart Failure • Metabolic Disorders • Nephrology • Obesity • Renal Disease

Effects of zibotentan and dapagliflozin combined in patients with compensated cirrhosis: A randomized placebo-controlled exploratory study. (PubMed, Br J Clin Pharmacol) - "Combined zibo/dapa was well tolerated and had a good safety profile in patients with compensated cirrhosis, but had no conclusive effect on HVPG."

Journal • Cardiovascular • Fibrosis • Hepatology • Hypertension • Immunology • Liver Failure • Metabolic Disorders • Portal Hypertension

Impact of Zibotentan and Dapagliflozin Combination Therapy on Lipid Biomarkers in Individuals with CKD (KIDNEY WEEK 2025) - "Conclusion In individuals with CKD, combination therapy with zibotentan and dapagliflozin improved key lipid parameters, notably reducing PCSK9, Lp(a) and ApoB levels, compared to dapagliflozin alone. These findings suggest potential cardiovascular benefits beyond albuminuria reduction."

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

Risk of CKD Progression in a Real-World Population Eligible for the ZENITH-High Proteinuria Trial (KIDNEY WEEK 2025) - P3 | "The efficacy of zibotentan and dapagliflozin combination therapy in preserving eGFR in patients with UACR >700 mg/g is being explored in the ZENITH-High Proteinuria study (ZENITH-HP; NCT06087835). The 2-year risk of HF or CKD hospitalizations was 34.3% (33.2–35.4); the 2-year risk of ASCVD events was 10.7% (10.0–11.5). Conclusion This analysis confirms the significant risk of CKD progression and cardiorenal and ASCVD events in patients with proteinuric CKD meeting key eligibility criteria for ZENITH-HP, emphasizing the importance of improving access to guideline directed therapies and the need for novel therapies in this population."

Clinical • Real-world • Real-world evidence • Atherosclerosis • Cardiovascular • Chronic Kidney Disease • Congestive Heart Failure • Diabetes • Diabetic Nephropathy • Heart Failure • Metabolic Disorders • Renal Disease • Type 1 Diabetes Mellitus • Type 2 Diabetes Mellitus

Effects of Zibotentan and Dapagliflozin Combination Therapy on Albuminuria and Fluid Parameters in CKD: Results from the ZODIAC Trial (KIDNEY WEEK 2025) - "Conclusion Zibo/dapa combination therapy reduced albuminuria in an additive manner, mitigated fluid retention, and was well tolerated. These findings support zibo/dapa combination as a promising strategy for kidney protection."

Combination therapy • Chronic Kidney Disease • Nephrology • Renal Disease

The emerging role of Oxadiazole derivatives as VEGFR and EGFR inhibitors in Cancer therapy. (PubMed, Bioorg Chem) - "For example, drug zibotentan, an oxadiazole ring-containing drug present in phase III clinical trials, has shown anticancer effects by slowing down cancer progression and improving survival rates in some patients. This review article highlights the importance of dual EGFR and VEGFR pathway inhibition, summarizes common methods for synthesizing oxadiazole ring derivatives, and discusses the VEGFR and EGFR inhibitory potential of oxadiazole derivatives reported between 2019 and 2025. The structure-activity relationship (SAR) studies and docking insights presented in this article could help medicinal chemists in designing and developing next-generation VEGFR and EGFR inhibitors."

Journal • Review • Oncology

Localization of the therapeutic targets for endothelin receptor antagonists and sodium-glucose co-transporter 2 inhibitors in the chronic liver disease, primary sclerosing cholangitis. (PubMed, Front Pharmacol) - "Ongoing clinical trials of portal hypertension in liver disease are testing the efficacy of a new treatment strategy combining ETA-selective antagonist zibotentan with SGLT2 inhibitor dapagliflozin. Both ETA, ETB and low levels of SGLT2 immunofluorescence localised to fibroblasts within the fibrous septa where bands of scar tissue can restrict hepatic blood flow, leading to cirrhosis. Both drug targets were retained in the key hallmarks of PSC pathology; ETA and SGLT2 staining within cholangiocytes undergoing ductal transformation and cells within the fibrotic septa, supporting the proposed benefit of combination treatment strategy."

Journal • Cardiovascular • Fibrosis • Hepatology • Hypertension • Immunology • Liver Failure • Oncology • Portal Hypertension

METABOLIC AND CARDIOVASCULAR EFFECTS OF ZIBOTENTAN AND DAPAGLIFLOZIN IN PATIENTS WITH CIRRHOSIS: A RANDOMIZED PLACEBO-CONTROLLED 6-WEEK STUDY (AASLD 2025) - "Six weeks of treatment with both zibo/dapa and zibo alone were well tolerated, with no significant difference in fluid retention-related events between the active arms. Dapagliflozin may mitigate fluid retention associated with a lower dose of zibo. Both active treatment groups lowered blood pressure and transaminase levels."

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

Unveiling the Anti-cancer Potential of Oxadiazole Derivatives: A Comprehensive Exploration of Structure-Activity Relationships and Chemico-Biological Insights. (PubMed, Med Chem) - "Overall, these results will prove to be a helpful and vital tool for medicinal chemists investigating and working with oxadiazoles for anti-cancer action."

Journal • Review • Oncology

NAP1L5 in acute myeloid leukemia: a prognostic biomarker and potential therapeutic target. (PubMed, Front Oncol) - "Drug sensitivity analysis identified NAP1L5 overexpression as a marker of resistance to Zibotentan, along with associations with 49 additional therapeutic agents. In vitro functional assays demonstrated that NAP1L5 overexpression promoted cellular proliferation, migration, and colony formation while concurrently inhibiting apoptosis, highlighting its oncogenic potential in AML pathogenesis. NAP1L5 emerges as a promising prognostic biomarker and therapeutic target in AML, offering potential for improved patient outcomes and precision treatment strategies."

Biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD4

Genetic variation in the endothelin eta receptor contributes to microvascular angina (ESC-WCC 2025) - "Methods 93 participants with microvascular angina were recruited prospectively from 10 hospitals in the United Kingdom to an observational sub-study of the Precision Medicine with Zibotentan in Microvascular Angina (PRIZE) trial [3]...No significant differences were detected in clinical variables between the other genotyped SNPs. Conclusions In a microvascular angina population, an EDNRA gene SNP, rs6842241, is associated with adverse clinical features, likely related to excess circulating ET-1."

Cardiovascular • Coronary Artery Disease • EDNRA

Zibotentan and Dapagliflozin Combination, EvAluated in Liver Cirrhosis (ZEAL Study) (clinicaltrials.gov) - P2 | N=205 | Terminated | Sponsor: AstraZeneca | Active, not recruiting ➔ Terminated; The study was ended earlier than planned due to a sponsor decision.

Monotherapy • Trial termination • Cardiovascular • Fibrosis • Gastroenterology • Hepatology • Hypertension • Immunology • Liver Cirrhosis • Portal Hypertension

Letter by Zhao Regarding Article, "Zibotentan in Microvascular Angina: A Randomized, Placebo-Controlled, Crossover Trial". (PubMed, Circulation) - No abstract available

Journal • Cardiovascular