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Anti-angiogenesis drugs are well known as being a growth area in oncology therapeutic development, however vascular disrupting targets or agents (VDA) are relatively unknown. VDA’s are a novel class of drug with the opportunity to have a greater efficacy in fighting cancerous tumors. This article looks at some of the VDA drugs in clinical development trials and the potential chances of success of this type of cancer treatment.
Anti-angiogenesis and Vascular Disrupting Agents in Oncology
In 1971, Dr Judah Folkman outlined the concept of fighting cancer by targeting the blood vessels that nourish the tumor by providing oxygen and nutrients. Anti-angiogenesis drugs are believed to work by regressing and preventing the formation of these blood vessels and ultimately limiting cancer tumor growth. Anti-angiogenesis oncology drugs such as Roche’s Avastin (bevacizumab) have been approved for fighting solid tumors in cancer treatment.
VDA’s work in a complimentary way to anti-angiogenesis drugs, but they have a different mode of action. VDA’s work by directly attacking the endothelial cells, that line the inside of blood vessels, and cause them to die via apoptosis. This is seen to work because tumor blood vessels have a high dependence on endothelial cells as opposed to normal blood vessels which have more support from connective tissue and muscle. The VDA is believed to bind to the tubulin protein found in the endothelial cells and as this binding builds up it causes the blood flow to diminish to the tumor. They are usually used in combination with chemotherapy and in particular are seen as working in lung cancer.
VDA Drugs in Development for Cancer Treatment, Notably for Lung Cancer
Whilst being a novel class of drug, there are and have been a few development programmes for VDA’s
OxiGene’s Zybrestat CA4P
Antisoma’s ASA404 (DMXAA)
Nereus Pharmaceutical’s Plinabulin (NPI-2358)
Sanofi Aventis Ombrabulin AVE8062
D6126 was discontinued according to Sui X. Cai
ZD6126 (ANG453) was discovered by scientists at Angiogene Pharmaceuticals and licensed to AstraZeneca for development. However, it was reported recently that AstraZeneca has discontinued the phase II clinical trials of ZD6126 “
Antisoma ASA404 Phase III for Lung Cancer
Antisoma’s ASA404 was the first VDA to enter Phase III but was discontinued during disappointing trials for non-small cell lung cancer NSCLC in combination with chemotherapy agent Taxotere (docetaxel). Antisoma stated "the planned interim analysis of data from the ATTRACT-1 phase III trial of ASA404 in previously untreated non-small cell lung cancer(NSCLC) has shown that continuation of the trial would be futile, as there is little or no prospect of demonstrating a survival benefit with ASA404 in this setting. The ATTRACT-1 trial will therefore be halted.’
This setback to Antisoma’s lead compound, caused a dramatic fall in their share price and was disappointing because Phase II results in NSCLC were encouraging. However, ASA404 had previously disappointed with Phase II results in ovarian cancer. The ovarian cancer results failed to improve either median time to tumor progression or one year survival rates, as opposed to chemotherapy (Taxotere) treatment alone.
Oxigene Zybrestat (CA4P) Phase II for Anaplastic Thyroid Cancer
OXiGENE have a VDA, Zybrestat (CA4P or fosbretabulin), in development which is being evaluated for solid tumors in multiple trials. Zybrestat works in a typical mode for VDA’s and OXiGENE are developing it for treatment in anaplastic thyroid cancer. Whilst Antisoma’s ASA404 was being tested with Docetaxel, Zybrestat is being tested in combination with a Roche’s anti-angiogenesis drug AVASTIN.
Zybrestat has provided good results in Phase II trials for ovarian cancer and in Septenber 2010, reported initial results for its phase II trial in anaplastic thyroid cancer. Unfortunately, the trial was only able to enrol 80 patients, as opposed to the intended 180. This means that the results of the trial cannot be declared to be statistically significant.
Patients were treated with a combination of zybrestat and chemotherapy and demonstrated a median overall survival of 5.1 months compared 4.1 months for similar patients treated with chemotherapy alone.
Whilst the results are positive, they are not a statistical demonstration of efficacy.
OXiGENE intends to release more analysis of the trial results later in 2010 or early 2011.
On November 19, OXiGENE released more data from the trial in NSCLC
"The updated analysis showed that the median time to progression for patients receiving ZYBRESTAT plus bevacizumab and chemotherapy was 9.5 months, compared with a median time to progression of 8.8 months for patients receiving bevacizumab and chemotherapy alone. Of the patients in the study arm (ZYBRESTAT combined with bevacizumab and carboplatin/paclitaxel chemotherapy), 50% achieved a partial response, compared with the control arm (bevacizumab and chemotherapy) of the trial, where only 38% of patients achieved a partial response. The combination regimen including ZYBRESTAT was observed to be well-tolerated with no significant cumulative toxicities when compared with the control arm of the study."
Nereus Pharmaceutical Plinabulin (NPI-2358)
According to Cai in ‘Small Molecule Vascular Disrupting Agents,’‘NPI-2358 is a synthetic analog of diketopiperazine phenylahistin (halimide), a natural product that was isolated from a marine and a terrestrial fungus Aspergillus’
Plinabulin binds to the colchicine-binding site of tubulin preventing polymerization and disrupting the microtubule network. Preclinical studies indicated plinabulin had a favorable safety and activity profile leading to the initiation of clinical trials.
Favorable data from early clinical studies lead to the initiation of a randomnized Phase II clinical trial in combination with docetaxel. This is similar to Antisoma’s ASA404 trial discussed above. The Nereus trial is ongoing and has an estimated primary completion date set for November 2010.
Sanofi Aventis Ombrabulin(AVE8062)
Ombrabulin is currently being investigated in phase III in refractory advanced soft tissue sarcoma. It is derived from the South African willow bush (Combretum caffrum), with potential vascular-disrupting and antineoplastic activities. In common with other VDAs Ombrabulin binds to the colchicine binding site of endothelial cell tubulin, Phase III studies are taking place in non small cell lung cancer, by Sanofi Aventis. In a phase I clinical trial, Ombrabulin in combination with docetaxel, proved well tolerated and preliminary anti-tumor activity was observed.
Prospects for VDAs, a Novel Class of Drug
The failure of the first drug in Phase III , Antisoma’s ASA404, has cast a cloud over VDA’s and on November 11 Antisoma declared that
"a scheduled interim analysis showed that the ATTRACT-2 trial should stop as ASA404 was unlikely to provide any benefit as a second-line treatment for non-small cell lung cancer."
When probabilities of a drugs success are to be calculated, it is often the mode of action and class of drug that is important rather than the target indication. Therefore, VDAs should still be classed as a novel type of drug.
Nevertheless, Plinabulin in Phase II has a primary completion date set for late 2010 and at a similar time Zybrestat has Phase II results to be fully analysed in anaplastic thyroid cancer. Initial results for Zybrestat are inconclusive due to trial size. Most exciting of all, is that a large cap Pharma, Sanofi-Aventis is trialling Ombrabulin in Phase III. However, despite large cap pharma co’s being more successful in Phase III, it should be noted that Ombrabulin is being tested in the same difficult target indication (NSCLC) as ASA404 proved unsuccessful in.