zibotentan (ZD4054) / 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

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

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

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=12 | Completed | Sponsor: AstraZeneca | Recruiting ➔ Completed | N=20 ➔ 12

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

Selective endothelin A receptor antagonism in chronic kidney disease: improving clinical application. (PubMed, Nephrol Dial Transplant) - "The first ERA (sparsentan) is now available for use in patients with immunoglobulin A (IgA) nephropathy, a specific type of kidney disease. Concomitant use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) may mitigate these adverse effects through their diuretic actions. The development of highly selective ETA antagonists, such as atrasentan and zibotentan, and the opportunities of combining these with SGLT2i, holds promise to optimize efficacy and safety of ERAs in clinical practice."

Journal • Review • Cardiovascular • Chronic Kidney Disease • Congestive Heart Failure • Diabetes • Diabetic Nephropathy • Fibrosis • Focal Segmental Glomerulosclerosis • Genetic Disorders • Glomerulonephritis • Heart Failure • IgA Nephropathy • Immunology • Inflammation • Metabolic Disorders • Nephrology • Obesity • Renal Disease • Type 2 Diabetes Mellitus • EDN1

A Comprehensive Review: Synthesis and Pharmacological Activities of 1,3,4-Oxadiazole Hybrid Scaffolds. (PubMed, Med Chem) - "This comprehensive review offers valuable insights into the synthesis and pharmacological applications of 1,3,4-oxadiazoles. It serves as a crucial resource for researchers exploring the development of new therapeutic compounds, with the ultimate goal of improving public health. The review builds on existing literature from the last two decades to present an exhaustive examination of the potential of 1,3,4-oxadiazole derivatives in drug development."

Journal • Herpes Zoster • Oncology • Varicella Zoster

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

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=20 | Recruiting | Sponsor: AstraZeneca | Not yet recruiting ➔ Recruiting | N=40 ➔ 20

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

Endothelin receptor antagonists in chronic kidney disease. (PubMed, Nat Rev Nephrol) - "In patients with type 2 diabetes and CKD, the selective ETA ERA, atrasentan, reduced albuminuria and kidney function decline...Moreover, combined administration of a low dose of the ETA-selective ERA, zibotentan, with the sodium-glucose cotransporter 2 (SGLT2) inhibitor, dapagliflozin, enhanced albuminuria reduction and mitigated fluid retention in patients with CKD. Notably, sparsentan and aprocitentan have received FDA approval for the treatment of IgA nephropathy and treatment-resistant hypertension, respectively. This Review describes our current understanding of the use of ERAs in patients with CKD to guide their optimal safe and effective use in clinical practice."

Journal • Review • Cardiovascular • Chronic Kidney Disease • Congestive Heart Failure • Glomerulonephritis • Heart Failure • Hypertension • IgA Nephropathy • Metabolic Disorders • Nephrology • Renal Disease • Type 2 Diabetes Mellitus • EDN1

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

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=40 | Not yet recruiting | Sponsor: AstraZeneca

New P1 trial • Fibrosis • Gastroenterology • Hepatology • Immunology • Liver Cirrhosis

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

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

Clinical • Combination therapy • Journal • Chronic Kidney Disease

The role of endothelin receptor antagonists in IgA nephropathy. (PubMed, Nephrology (Carlton)) - "Here, we review current evidence, including the use of sparsentan, atrasentan and zibotentan in IgAN. Recent trails of combination therapy including SGLT2 inhibitors and ERAs suggest possible benefit in further reduction of proteinuria and reducing ERA fluid-retention side effects although more evidence is needed for clinical applications."

Journal • Review • Glomerulonephritis • IgA Nephropathy • Nephrology • Renal Disease

Zibotentan in Microvascular Angina: A Randomized, Placebo-Controlled, Crossover Trial. (PubMed, Circulation) - " Among patients with microvascular angina, short-term treatment with a relatively high dose (10 mg daily) of zibotentan was not beneficial. Target-related adverse effects were common."

Journal • Cardiovascular • Diabetes • Metabolic Disorders • EDN1

Zibotentan in microvascular angina: a randomized, placebo-controlled, crossover trial (ESC 2024) - "• Conclusion(s) In conclusion, daily administration of 10 mg zibotentan for 12 weeks did not enhance exercise duration and was commonly associated with adverse effects related to fluid retention. Further trials exploring lower zibotentan doses in combination with agents to mitigate fluid retention, and longer treatment durations, are warranted."

Clinical • Cardiovascular • EDN1