Zibotentan (ZD4054)

Mechanism of action: Endothelin receptor A (ETA) antagonist


Preclinical pharmacology

Zibotentan, ZD4054, is a potent antagonist of ETA (IC50 = 13nM) with no effect at the ETB receptor nor at a broad panel of other targets. In a range of tumour cell lines including osteoblast, vascular myoepithelial, prostate, breast, and ovarian, ZD4054 inhibits pro-oncologic behavior such as inhibition of apoptosis and cellular proliferation. In murine tumor xenograft models of prostate, ovarian, breast, and other cancers, ZD4054 (either 10mg/kg/day, ip or 50mg/kg/day, po) inhibited tumour cell proliferation and mortality. ZD4054 also inhibited blood vessel growth into the above tumour explants at concentrations of 25 and 50mg/kg/day, po.


Safety and tolerability

ZD4054 has been administered orally in healthy volunteers in single doses up to 240mg and multiple doses of up to 100mg daily for 14 days. It has been tested in multiple clinical trials and in Phase 3 prostate cancer patients with bone metastases at doses of 10mg and 15mg QD for up to 2 years. The most common adverse events were ETA mechanism related, including peripheral oedema, headache, and nasal congestion/rhinitis. Analysis of the Phase 3 study in metastatic resistant prostate cancer indicated an increased risk and reduced time to onset of pneumonia in the patient group exposed 10mg QD.

Preclinical safety studies up to 12 month duration have been performed.


Clinical pharmacology

In healthy male volunteers, ZD4054 (10 and 30mg) inhibited an ETA receptor mediated forearm vasoconstriction response induced by ET-1 infusion while having no effect on ETB receptors at doses of up to 240mg (no evidence of increases in circulating ET-1 levels; ET-1 is cleared through binding to ETB receptors). No efficacy was seen in Phase 3 oncology trials at 10mg (~26 x IC50 in plasma), although this dose produced ETA mechanism related AEs such as nasal congestion, peripheral oedema, and headache indicating target engagement.


Suitable for and exclusions

The reproductive toxicology package indicates a risk of fetal toxicity. The inclusion of women of child-bearing potential would need to be assessed for any proposal based on the risk-benefit and the use of appropriate highly effective contraception. Preclinical CNS and CV safety study findings indicate that patients with a previous history of epilepsy, other CNS adverse events, or neurologic symptoms or signs consistent with acute or evolving spinal cord compression or CNS metastases should be excluded as should patients with NYHA grade II heart failure. ZD4054 is largely renally cleared, so the dose in patients with moderate to severe renal impairment would have to be re-evaluated.

AstraZeneca is not keen on pursuing ZD4054 for additional preclinical or clinical oncology indication research at this time.

Additional Information


Clinical trials for this compound

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Publications for this compound

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PubMed.gov

 

 


Gene information from the NCBi

This compound works on the following genes: