zibotentan (ZD4054) / AstraZeneca - LARVOL DELTA

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

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

Journal • Cardiovascular

Integrative Multi-Omics Analysis and Experimental Validation Identify SPOP as a Prognostic Biomarker and Immune Regulator in Lung Adenocarcinoma. (PubMed, J Cancer) - "Drug sensitivity analysis suggested that low SPOP expression is linked to increased sensitivity to zibotentan and 5-fluorouracil. SPOP is a reliable independent prognostic biomarker in LUAD, influencing tumor progression, immune microenvironment, and therapeutic response. Our findings support the potential of SPOP as a novel therapeutic target for personalized treatment strategies in LUAD."

Biomarker • Journal • Immune Modulation • Immunology • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • NANOG • PVR • SPOP

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

A Study to Investigate the Blood Concentrations of 4 Different Oral Doses of Zibotentan in Healthy Non-Asian and Japanese Participants (clinicaltrials.gov) - P1 | N=30 | Completed | Sponsor: AstraZeneca | N=12 ➔ 30

Enrollment change • Fibrosis • Gastroenterology • Hepatology • Immunology • Liver Cirrhosis

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