Zibotentan

• Zibotentan is an endothelin A receptor antagonist, meaning it blocks the action of endothelin-1.
• It was primarily investigated for the treatment of advanced prostate cancer and other solid tumors.
• The drug aimed to reduce tumor progression, bone pain, and improve patient outcomes by inhibiting endothelin signaling.
• Clinical trials showed mixed results, with some studies not meeting primary endpoints for overall survival.
• Common side effects included fluid retention (edema) and cardiovascular events.

What is Zibotentan? Drug Class and Mechanism of Action

Zibotentan is an orally active, selective endothelin A (ETA) receptor antagonist. This means it works by blocking the binding of endothelin-1 (ET-1) to the ETA receptor. Endothelin-1 is a potent vasoconstrictor and a peptide hormone that plays a significant role in various physiological and pathological processes, including cell proliferation, angiogenesis (formation of new blood vessels), and bone remodeling, all of which are relevant in cancer development and progression.

The Zibotentan drug class and mechanism specifically target the ETA receptor, which is often overexpressed in various cancer types, including prostate cancer. By inhibiting this receptor, Zibotentan aims to counteract the pro-tumorigenic effects of ET-1, such as promoting tumor cell growth, survival, and metastasis, as well as reducing tumor-induced bone pain. This targeted approach seeks to disrupt critical signaling pathways that contribute to cancer advancement.

What is Zibotentan Used For?

Zibotentan was primarily investigated for its potential use in treating advanced prostate cancer, particularly in patients with metastatic disease. The rationale behind its use in prostate cancer stemmed from evidence suggesting that the endothelin system is highly active in this malignancy, contributing to tumor growth, spread to bone, and associated pain. Clinical trials explored its efficacy as a monotherapy and in combination with other treatments.

Beyond prostate cancer, Zibotentan was also evaluated in early-phase clinical trials for other solid tumors, including ovarian cancer and non-small cell lung cancer. The goal was to assess its ability to slow disease progression, alleviate symptoms such as bone pain, and potentially improve overall survival or progression-free survival in these patient populations. However, its development largely focused on its application in prostate cancer due to the strong biological rationale and unmet medical needs in this area.

Zibotentan Side Effects, Safety, and Clinical Trials

The safety profile of Zibotentan was characterized during its extensive clinical development program. Common Zibotentan side effects and safety concerns included fluid retention (edema), which could manifest as peripheral edema or pulmonary edema, and cardiovascular events such as heart failure and hypertension. These effects are consistent with the known physiological roles of the endothelin system, which influences vascular tone and fluid balance. Patients receiving Zibotentan were often monitored for these potential adverse reactions.

Zibotentan clinical trials information indicates that the drug underwent several Phase II and Phase III studies. For instance, the ‘STRIVE’ and ‘SYNERGY’ Phase III trials investigated Zibotentan in men with metastatic castration-resistant prostate cancer. While some trials showed a reduction in bone pain or improvements in certain biomarkers, the primary endpoints related to overall survival were not consistently met across all studies. As a result, Zibotentan did not receive regulatory approval for widespread clinical use and its development was discontinued by the manufacturer. This outcome highlights the challenges in translating promising biological mechanisms into clinically significant survival benefits for complex diseases like cancer.