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Oxigene's Zybrestat cuts tumour blood flow

By Pete Mansell , 06-Jun-2007

Oxigene's potentially first-in-class cancer drug is showing promising clinical results and could rival a drug Novartis' recently spent nearly a billion dollars on.

Data from a Phase II clinical trial have shown that combination therapy with Oxigene's Zybrestat (combretastatin A4 phosphate/CA4P) can significantly reduce blood flow in tumours. The results were released at the American Society of Clinical Oncology (ASCO) conference, held in Chicago this week.

 

 

 

Both Zybrestat and Novartis' AS1404 (5,6-dimethyl xanthenone 4-acetic acid, DMXAA) are investigative vascular disrupting agents (VDAs) designed to prevent tumours receiving the blood they need to survive. AS1404 was originally developed by UK biopharmaceutical company Antisoma, and this new therapeutic approach received a strong endorsement in April when licensed it from them in a deal worth up to $890m (€660m).

 

 

 

Both drugs are in Phase II trials and either could be the first ever VDA on the market, although perhaps the wieght - and money - of a pharma giant behind AS104 might give it the edge.

 

 

 

On the other hand, Oxigene, a US biopharmaceutical company developing novel small-molecule therapeutics for cancer and eye diseases, recently reached agreement with the Food and Drug Administration (FDA) on a Special Protocol Assessment for a Phase II/III pivotal study of Zybrestat in anaplastic thyroid cancer (ATC).

 

 

 

This means that Oxigene's Phase II/III study design is acceptable to the agency and sufficiently robust to form the basis of a regulatory approval, providing pre-specified efficacy results are achieved. The company plans to start enrolment this month for the multi-centre trial, in which Zybrestat combined with paclitaxel and carboplatin will be compared with paclitaxel and carboplatin alone in some 180 patients.

 

 

 

Currently there are no approved treatments for ATC, a high-grade, aggressive neoplasm that makes up 1-2 per cent of all primary thyroid malignancies. An estimated 1,000-4,000 new cases of ATC occur in the US and Europe combined each year. Newly diagnosed patients have a median life expectancy of about three months.

 

 

 

This was the first full dataset from the Phase II trial of Zybrestat in combination with the standard chemotherapy regimen paclitaxel and carboplatin. Two dose regimens of Zybrestat were studied in the trial - 45mg/m2 and 63mg/m2 in combination with paclitaxel and carboplatin.

 

 

 

Both were well tolerated, demonstrated anti-tumour activity and reduced tumour blood flow by 46 per cent and 19 per cent respectively. Zybrestat is designed selectively to target and disrupt tumour vasculature, depriving the tumour of oxygen and causing the death of tumour cells. It is a synthetic prodrug originally derived from the root bark of the Cape Bushwillow (Combretum caffrum) tree.

 

 

 

The sharpest reductions in tumour blood flow (73 per cent and 79 per cent) were seen in the two patients with ATC, the lead indication for Zybrestat. The Phase II study enrolled 13 patients in total with advanced imageable malignancies, who were evaluated with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) prior to and 24 hours after the first dose of Zybrestat.

 

 

 

Meanwhile, Novartis' AS104 is currently in Phase II trials for non-small cell lung cancer as well as prostate and ovarian cancers. It has a different mechanism of action from combretastatin A4, as it down-regulates the genes involved in tubulogenesis, leading to the formation of imperfect blood vessels and increasing the probability of apoptosis in the endothelial cells that line the inside blood vessels.

 

 

 

The drug also triggers a cascade of vasoactive molecules including tumour necrosis factor and serotonin. The two effects combined cause a rapid shutdown of blood flow to the tumour, resulting in extensive tumour necrosis.

 

 

 

Instead, Zybrestat exerts its effect by homing in on immature endothelial cells in tumour-associated blood vessels and disrupting the internal skeleton that gives these cells their characteristic flat shape. In response, the cells change to a rounded, bloated profile that effectively plugs the capillaries and obstructs the blood flow feeding the tumour.

 

 

 

A second abstract distributed at the ASCO annual meeting reported preliminary data from Oxigene's Phase I study of OXi4503, a second-generation VDA with potential intrinsic cytotoxicity. These indicated that OXi4503 is tolerated at doses of up to 5mg/ m2 without dose-limiting toxicity. Changes in functional activity were also observed in three of the 11 patients studied to date.

 

 

 

Preclinical research with OXi4503 suggests that it not only shuts down tumour blood flow but can also be converted by an ortho-quinone metabolite into a compound that may help to kill off the remaining tumour cells at the periphery of the tumour through direct cytotoxic activity, Oxigene says.

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