ASA404
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Overview
ASA404 (DMXAA, formerly AS1404)
ASA404 is a cancer drug produced by Antisoma for Prostate Cancer
Details
ASA404
ASA404 (DMXAA) is a small-molecule 'vascular disrupting agent' (VDA) that selectively disrupts established tumour blood vessels. It is currently in clinical trials for lung and prostate cancers. Antisoma has licensed the world-wide rights to ASA404 to Novartis AG. Novartis is now responsible for all further development work on the drug. Antisoma has an option to co-commercialise the drug with Novartis in the United States.
Targeting established tumour blood vessels
Solid tumours rely on a network of blood vessels in order to survive and grow. ASA404 targets established tumour blood vessels causing apoptosis (death) of vessel endothelial cells and the release of vasoactive molecules including serotonin, TNF and other cytokines. The action of ASA404 is distinct from that of angiogenesis inhibitors, which inhibit the formation of new tumour blood vessels.
Potential in combination with other cancer treatments
The therapeutic potential of ASA404 lies in combination with cytotoxic agents and other cancer treatments. Preclinical tests have shown synergistic (more than additive) effects with such combinations, and they have now become the focus for human clinical trials.
Clinical trials
Antisoma has conducted phase II trials with ASA404 in lung, prostate and ovarian cancers. Three randomised studies, each including about 70 patients, have evaluated the addition of ASA404 to standard chemotherapies in these cancers. Half the patients in each study received chemotherapy alone and half chemotherapy plus ASA404. The groups were then compared on various measures of safety and efficacy.
In addition, a single-arm 30-patient confirmatory trial has evaluated a higher dose of ASA404 in combination with chemotherapy in lung cancer.
Addition of ASA404 to chemotherapy was generally well tolerated in these trials. Efficacy findings in the various cancers are described below.
Novartis plans to start enrolling patients into a phase III study in non-small cell lung cancer early in 2008.
Prostate cancer
A randomised phase II study has been conducted in hormone-refractory metastatic prostate cancer. This compares patients receiving docetaxel alone with patients receiving docetaxel plus ASA404. The PSA response rate (proportion of patients showing a sustained >50% reduction in levels of the biomarker PSA) was markedly higher in patients receiving the combination than in patients receiving chemotherapy alone (59% vs 37%). Details of the PSA findings have been presented at conferences (see ASCO poster presentation). It has now also been announced that tumour response rates in patients assessable by 'RECIST' were higher in patients who received ASA404 and that time to disease progression was marginally longer in patients who received ASA404. Median survival data are expected in the second half of 2008.
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Articles
PharmaTimes (KC) 13-Apr-08
References
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