ASA404 Vascular Disrupting Agent for Solid Tumours

ASA404 is a vascular disrupting agent (VDA) that is being co-developed by Antisoma and Novartis as a treatment for a range of solid tumours. Originally discovered by scientists in New Zealand, ASA404 was licensed to Antisoma in 2001. Novartis subsequently acquired worldwide rights to ASA404 in 2007.

On the back of encouraging Phase II trials results in advanced lung cancer, ASA404 is now scheduled to enter Phase III trials in patients with non-small cell lung cancer (NSCLC). If these prove equally successful then filing for regulatory approval is likely in 2010 or 2011.

In September 2009, Novartis announced that it had completed patient enrolment for its Phase III clinical trial. Approximately 1,200 patients have been enrolled for the trial.

VDAs target established tumour vasculature

The concept of attacking tumours by cutting off their blood supply was first described in the early 1970s and subsequently led to the development of a new class of anticancer drugs called angiogenesis inhibitors.

These drugs, which are now in clinical use, work by preventing tumours from developing a blood supply – a pre-requisite for tumour growth and metastasis (tumour spreading).

VDAs differ from angiogenesis inhibitors in that they are designed to attack the established blood vessel network within a tumour rather than preventing the growth of new blood vessels from the viable tumour rim.

Antisoma's ASA404 (5,6-dimethylxanthenone-4-acetic acid) is a small molecule VDA that in preclinical studies demonstrated additive or supra-additive anti-tumour effects when combined with standard cytotoxic agents, most notably taxanes.

Efficacy in NSCLC

NSCLC, the most common type of lung cancer, is an aggressive disease that has proved notoriously difficult to treat. Despite the availability of new, targeted drugs for lung cancer, prognosis for many patients remains poor.

Phase II trials in NSCLC patients suggest that the addition of ASA404 to conventional treatment with carboplatin and paclitaxel significantly enhances overall clinical effectiveness. Indeed, the companies believe that the addition of ASA404 to chemotherapy has produced one of the largest increases in median survival ever reported in advanced lung cancer patients.

Results from the randomised Phase II trial, in which patients received a 1,200mg/m2 dose of ASA404 in combination with chemotherapy, showed median survival was 14.0 months in the ASA404 treatment arm compared with 8.8 months in those receiving chemotherapy alone.

A subsequent open-label extension to the randomised trial, in which a higher dose of 1,800mg/m2 ASA404 was used in combination with carboplatin and paclitaxel, confirmed these findings. Median survival was 14.9 months and median time to tumour progression 5.5 months, while the overall tumour response rate was 37.9%.

In April 2008, Novartis announced the start of Phase III clinical trial ATTRACT-1 (Antivascular Targeted Therapy: Researching ASA404 in Cancer Treatment) for ASA404. The trial is being conducted in more than 20 sites in 200 countries. The trial is a randomised, double-blind, placebo-controlled, study of ASA404 with paclitaxel and carboplatin. It is examining ASA404 as a first-line treatment for NSCLC (both squamous or non-squamous histology).

In January 2009, Novartis launched Phase III clinical trial ATTRACT-2 for ASA404. It will examine ASA404 as a second-line treatment for NSCLC.

The trial will recruit 900 patients who have undergone chemotherapy treatment alone and patients who have received chemotherapy along with bevacizumab or cetuximab as a first-line treatment. The primary endpoint of the trial is overall survival. The trial is expected to be completed in 2011.

Potential in other solid tumours

Although early clinical trials in patients with ovarian cancer failed to produce the positive results seen with ASA404 in the lung cancer trials, encouraging results have been reported in prostate cancer patients.

Improvements over chemotherapy alone were observed in a 74-patient open-label study, in which chemotherapy-naive patients were randomised to ASA404 plus docetaxel or docetaxel alone (standard therapy).

In this population of patients with progressive, hormone-refractory metastatic prostate cancer, treatment with ASA404 plus docetaxel was associated with a higher PSA response compared with standard therapy alone (57% vs. 35%).

In addition, fewer patients in the combination treatment arm showed PSA progression.

Further trials are needed to confirm these early indications of efficacy in prostate cancer.

Marketing commentary

VDAs, none of which are yet approved as a cancer treatment, are seen as a potentially attractive new class of anti-cancer agents, able to potentiate the effectiveness of existing anticancer drugs. To date, ASA404 has demonstrated efficacy in combination with taxanes, a widely used class of anticancer agents.