ASA404 (DMXAA, formerly AS1404)
ASA404 (DMXAA) is a small-molecule Tumour-Vascular Disrupting Agent (Tumour-VDA) that selectively disrupts established tumour blood vessels. It is currently in phase III clinical trials for lung cancer and will enter trials in breast cancer later in 2009. Antisoma has licensed the world-wide rights for ASA404 to Novartis AG. Novartis is now responsible for all further development work on the drug.
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 tumour endothelial cells and the local release of vasoactive molecules including tumour necrosis factor (TNF) and nitric oxide. This results in rapid reduction in blood flow to the tumour, leading to tumour necrosis. The action of ASA404 is distinct from that of angiogenesis inhibitors, which inhibit the formation of new tumour blood vessels.
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Latest presentations
- Lung cancer poster presentation at ASCO, 2008 (PDF, 111 KB, opens a new browser window)
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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. Antisoma has conducted phase II trials with ASA404 in combination with standard chemotherapy in lung, prostate and ovarian cancers.
Lung cancer - the lead indication for ASA404
The lead indication for ASA404 is non-small cell lung cancer. Novartis is conducting two pivotal phase III trials in this indication, which will build on supportive data from phase II studies carried out previously by Antisoma, as described below.
A randomised phase II study in lung cancer included patients with stage IIIb/IV non-small cell lung cancer of any histology (NCT00832494). Median survival was 14.0 months in patients receiving ASA404 plus carboplatin and paclitaxel chemotherapy, compared with 8.8 months in patients receiving chemotherapy alone. Addition of ASA404 to chemotherapy was generally well tolerated.
A single-arm study was conducted as an extension to the phase II trial. This also included non-small cell lung cancer patients with stage IIIb or IV disease of any histology. In this study, an 1800mg/m
2; dose of ASA404 was combined with carboplatin and paclitaxel (whereas all the randomised studies in lung and other cancers used a 1200mg/m
2 dose). Median survival was 14.9 months.
Data from these phase II studies show that patients with both squamous and non-squamous types of non-small cell lung cancer experienced a survival benefit with ASA404.