What Is Zibotentan?
Zibotentan is a drug that has been studied in 18 clinical trials involving a total of 3,613 participants. It is an endothelin receptor antagonist. This means it works by blocking the action of endothelin, a natural substance in the body that can cause blood vessels to narrow. By blocking endothelin, zibotentan may help to relax blood vessels and improve blood flow.
While specific approvals are not detailed in the provided data, zibotentan has been investigated for various conditions. These include liver cirrhosis, chronic kidney disease, and peripheral arterial disease. It has also been studied in healthy participants and those with hepatic impairment to understand its effects and safety profile.
Many trials have studied zibotentan in combination with dapagliflozin, often as a fixed-dose combination. This suggests potential uses where both mechanisms might be beneficial, such as in conditions affecting the kidneys or liver. The first trial involving zibotentan began on April 17, 2006, and research is ongoing, with the latest trial expected to conclude in February 2026.
Uses and Conditions Under Study
Zibotentan has been investigated across a range of medical conditions, with a focus on its potential effects on the cardiovascular system, kidneys, and liver. A total of 18 clinical trials have explored its uses.
For kidney-related conditions, zibotentan has been studied in 3 trials for Chronic Kidney Disease and 2 trials for Chronic Kidney Disease With High Proteinuria. Chronic kidney disease involves a gradual loss of kidney function, and high proteinuria indicates excessive protein in the urine, often a sign of kidney damage. As an endothelin receptor antagonist, zibotentan may help by reducing pressure within the kidneys or improving blood flow, potentially slowing disease progression.
Liver health has also been a focus, with 3 trials for Liver Cirrhosis and 1 trial for Hepatic Impairment. Liver cirrhosis is a late stage of scarring of the liver caused by various liver diseases. Hepatic impairment refers to reduced liver function. Zibotentan's mechanism might offer benefits by affecting blood flow within the liver or reducing fibrosis.
Cardiovascular and circulatory conditions include Intermittent Claudication (1 trial), Microvascular Angina (1 trial), and Peripheral Arterial Disease (1 trial). Intermittent claudication and peripheral arterial disease involve reduced blood flow to the limbs, causing pain. Microvascular angina affects the small blood vessels of the heart. Zibotentan's ability to relax blood vessels could improve circulation and alleviate symptoms in these conditions.
Additionally, zibotentan was investigated in 1 trial for Patients With Advanced Ovarian Cancer Sensitive to Platinum-based Chemotherapy. This suggests potential exploration of its effects beyond cardiovascular applications, possibly related to tumor blood supply or other cellular pathways.
Studies have also included 1 trial with Healthy Participants and 1 trial with Healthy Female Participants. These trials are typically conducted to understand how the drug is absorbed, distributed, metabolized, and excreted in the body, as well as to assess its safety profile in individuals without the target disease.
Dosing
Zibotentan has been studied in various forms and dosages across its clinical trials. The drug is primarily administered orally, either as an oral tablet or a capsule.
In some studies, zibotentan has been investigated as a single agent. For example, participants in one trial received 4 different single doses of zibotentan orally on separate occasions to evaluate its effects. Another trial specifically mentioned a dose of Zibotentan 15 mg when combined with docetaxel for certain conditions.
Many trials have explored zibotentan in a fixed-dose combination (FDC) with dapagliflozin. In these studies, participants received zibotentan/dapagliflozin in specific combinations, referred to as "Dose A" or "Dose B," indicating different strengths or ratios of the two drugs. Examples include "Zibotentan Dose A + Dapagliflozin" and "Zibotentan Dose B + Dapagliflozin." Placebo capsules matching zibotentan and placebo tablets matching dapagliflozin were also used in these studies to ensure proper comparison.
The specific dosing regimen, including the exact strength and frequency of administration, varies depending on the condition being studied and the design of each clinical trial. The data provided does not specify standard adult or pediatric doses, as the information primarily reflects investigational use within clinical study protocols.
Side Effects
The most common side effect reported in clinical trials for Zibotentan was anemia, affecting 51.7% of patients taking the drug, compared to 43.1% on placebo. Other frequently reported side effects included:
- Neutropenia, experienced by 44.8% of patients on Zibotentan, versus 37.9% on placebo.
- Leukopenia, affecting 34.5% of patients on Zibotentan, compared to 25.9% on placebo.
- Drug hypersensitivity, reported by 25.9% of patients taking Zibotentan, versus 17.2% on placebo.
- Constipation, observed in 25.5% of patients on Zibotentan, compared to 23.2% on placebo.
- Peripheral edema (swelling), occurring in 22.4% of patients taking Zibotentan, versus 8.6% on placebo.
- Headache, experienced by 13.8% of patients on Zibotentan, compared to 7.7% on placebo.
Some side effects were reported at similar or lower rates in patients taking Zibotentan compared to placebo. For instance, nausea was reported by 48.3% of Zibotentan patients versus 53.4% on placebo, and fatigue by 34.5% of Zibotentan patients versus 46.6% on placebo.
Clinical Trial Results
Advanced Ovarian Cancer
In a study (NCT00929162) evaluating Zibotentan (ZD4054) plus chemotherapy (paclitaxel and carboplatin) in patients with advanced ovarian cancer, the median progression-free survival was 7.6 months for patients receiving Zibotentan plus chemotherapy, compared to 10.0 months for those receiving placebo plus chemotherapy. The tumor response rate was also lower in the Zibotentan group, with 21 participants responding compared to 34 participants in the placebo group.
Chronic Kidney Disease (CKD)
The ZENITH-CKD trial (NCT04724837) investigated Zibotentan in combination with dapagliflozin for the treatment of CKD. After 12 weeks, patients treated with Zibotentan 1.5 mg plus dapagliflozin experienced an average reduction in systolic blood pressure of -11.0 mmHg from baseline, compared to a -3.4 mmHg reduction in the placebo plus dapagliflozin group. Diastolic blood pressure also saw greater reductions, with Zibotentan 1.5 mg plus dapagliflozin leading to a -6.8 mmHg change, versus -1.4 mmHg for placebo plus dapagliflozin.
Additionally, Zibotentan plus dapagliflozin led to greater improvements in urinary albumin to creatinine ratio (UACR), a marker of kidney health. At week 12, the geometric mean change in UACR from baseline was 0.48 mg/g for Zibotentan 1.5 mg plus dapagliflozin, compared to 0.72 mg/g for placebo plus dapagliflozin. A lower UACR indicates less albumin in the urine, which is a positive outcome for kidney function.
Cirrhosis
A Phase IIb study (NCT06269484), ZEAL-UNLOCK, assessed the safety of Zibotentan and dapagliflozin in patients with cirrhosis. The combination of Zibotentan and dapagliflozin significantly reduced blood pressure. The least squares mean change in systolic blood pressure was -12.0 mmHg for the combination therapy, compared to -2.6 mmHg for Zibotentan alone and -0.1 mmHg for placebo. Diastolic blood pressure also saw a greater reduction of -9.1 mmHg with the combination, versus -2.5 mmHg for Zibotentan alone and an increase of 1.8 mmHg for placebo.
However, the study also noted that Zibotentan, both alone and in combination with dapagliflozin, was associated with increased fluid retention compared to placebo. For example, 14 participants in both the Zibotentan alone and Zibotentan/dapagliflozin groups met a composite endpoint for fluid retention (including weight gain, increased total body water, or increased diuretic use), compared to 6 participants in the placebo group. The mean change in total body water increased by 0.66 L with Zibotentan alone and 0.36 L with Zibotentan/dapagliflozin, while it decreased by 0.36 L with placebo.
Currently Recruiting Trials
Zibotentan is currently being investigated in clinical trials to understand its potential benefits for patients with specific conditions. These studies are crucial for gathering more information about how Zibotentan works, its safety, and its effectiveness, helping to determine if it could become a new treatment option for those in need. Participating in a clinical trial offers an opportunity to contribute to medical research and potentially access new treatments.
One important study actively seeking participants is NCT06942910, sponsored by AstraZeneca. This is a Phase 2 trial, which means researchers are evaluating the drug's effectiveness and safety in a larger group of people, while also working to determine the most appropriate dosage. The study is titled "A Study to Investigate the Effects of Zibotentan/Dapagliflozin Combination Compared to Dapagliflozin Alone in Adult Participants With Chronic Kidney Disease and High Proteinuria."
This trial is specifically designed for adult participants living with Chronic Kidney Disease who also experience high proteinuria, a condition where too much protein is found in the urine, indicating kidney damage. Participants will receive either a combination of Zibotentan and Dapagliflozin at one of two specific dosages, or Dapagliflozin alone. By comparing these different treatment approaches, the study aims to understand if adding Zibotentan to Dapagliflozin offers additional benefits for managing this complex kidney condition. The study plans to enroll approximately 224 participants, allowing researchers to gather robust data on the potential impact of the Zibotentan/Dapagliflozin combination. If you are an adult aged 18 years or older and have Chronic Kidney Disease with high proteinuria, you may be eligible to participate and contribute to this important research.
Where to Participate
Currently, there are no specific study sites or locations listed for the Zibotentan clinical trial NCT06942910. This information is typically updated as trials progress and recruitment begins in various regions. Interested individuals should check the official clinical trial registry for the most current site availability.
For this particular study, eligibility criteria specify that participants must be adults aged 18 years. The study is open to participants of all genders. It is important to note that this trial is not seeking healthy volunteers; participants must have Chronic Kidney Disease with high proteinuria. The study is also not designed for children.
Development Timeline
The development journey of Zibotentan began on April 17, 2006, with the initiation of its first clinical trial. Since then, Zibotentan has been the subject of 18 clinical trials, involving a total of 3,613 participants across various studies, with the latest trial projected to conclude on February 11, 2026.
Early research for Zibotentan primarily focused on conditions such as IBS-C and hyperphosphatemia. Over time, the scope of investigation broadened significantly. The drug's development pipeline expanded to explore its potential in a wide range of conditions, including Chronic Kidney Disease With High Proteinuria, Hepatic Impairment, Renal Impairment, and Scleroderma. Researchers also investigated Zibotentan for Microvascular Angina, Intermittent Claudication, Peripheral Arterial Disease, and more serious conditions like Prostate Cancer, Advanced Ovarian Cancer Sensitive to Platinum-based Chemotherapy, Advanced Solid Malignancies, and Colorectal Cancer. Studies also included Healthy Participants and Healthy Female Participants to understand the drug's general profile.
The majority of Zibotentan's clinical development has occurred in Phase 2, with 10 trials reaching this stage, indicating a significant effort to evaluate its effectiveness and safety in specific patient populations. There have also been 7 Phase 1 trials, typically focused on initial safety and dosage, and 1 Phase 3 trial, which is a large-scale study designed to confirm efficacy and monitor side effects in diverse populations. The primary sponsor driving Zibotentan's development has been AstraZeneca, leading 13 of the 18 trials, with contributions from academic institutions like Cardiff University, NHS Greater Glasgow and Clyde, University College, London, University Medical Center Groningen, and the University of Virginia.