|
This "Information for Clinicians" section of the Azixa™ (verubulin, MPC‑6827) GBM Clinical Trials website is intended primarily for the use of healthcare professionals.
Azixa™ (verubulin, MPC-6827) is an investigational new cancer drug being developed by Myrexis, Inc. for the treatment of advanced primary and metastatic tumors.
Azixa is a novel, small-molecule that acts as a microtubule destabilizing agent, causing arrest of cell division and programmed cell death, or apoptosis, in cancer cells [1]. Azixa has also been shown to be a vascular disrupting agent (VDA) in a mouse model of human ovarian cancer [5]. Thus, Azixa has a dual mode of action; it induces apoptosis and reduces blood supply to the tumor. Importantly, in non-clinical studies, Azixa has demonstrated the unique ability to effectively cross the blood-brain barrier and accumulate in the brain at levels as much as 30-fold that in plasma and does not appear to be a substrate for multiple drug resistance pumps [1,2]. Azixa is currently being tested in clinical studies in patients with glioblastoma multiforme and metastatic melanoma.
Back to top
Preclinical Studies
In vitro mechanism of action studies have shown that Azixa binds to tubulin and destabilizes microtubules, which are cellular structures that play an important role in cell division and proliferation. This leads to inhibition of cell division and apoptosis [1]. However, unlike other tubulin binding drugs, such as vincristine, vinblastine and vinorelbine, and the chemotherapeutic class of drugs known as taxanes, such as paclitaxel and docetaxel, Azixa does not appear to be a substrate for multidrug resistance pumps. The activity of Azixa in multidrug resistant cell lines was similar to its activity in nonresistant cell lines [2]. Azixa has demonstrated potent activity in multiple cancer cell types, including glioma, melanoma, colon cancer, pancreatic cancer, breast cancer and ovarian [1,2]. In mice, Azixa significantly inhibited the growth of a variety of subcutaneously implanted tumor lines [4].
Azixa has also been shown to act as a VDA in a mouse model of human ovarian cancer [5]. Thus, Azixa has a dual mode of action; it induces apoptosis and acts as a VDA, resulting in tumor cell death. VDAs have been established to reduce interstitial pressure in the tumor microenvironment which may increase local exposure to cytotoxic chemotherapy. Consistent with this hypothesis, Azixa acts synergistically with the chemotherapeutic agent carboplatin in this mouse model of ovarian cancer. Accordingly, we believe Azixa has the potential to be used either in combination with other cytotoxic chemotherapies or as a single agent [5].
The distribution of Azixa into the CNS was evaluated in mice and the time to maximum drug concentration was the same in plasma and brain tissue, indicating that Azixa distributed rapidly into the CNS. Remarkably, Azixa concentration in the brain was 14 fold that in the plasma [1]. Similar studies were performed in dogs and demonstrated a 30 fold higher concentration in the brain. These data suggest that it is possible to reach therapeutic drug concentrations of Azixa in the CNS with minimal systemic exposure. Based on these results, we tested the anti-tumor activity (tumor growth and survival) of Azixa in a mouse model in which human glioma cells had been implanted in the brain. This study showed a statistically significant reduction in tumor burden and a statistically significant increase in survival when compared to vehicle treated mice [7].
Back to top
About Multiple Drug Resistance
Cancer cells may become resistant to anti-cancer drugs through a cellular function that actively secretes drug from the cell. The function is carried out by multiple drug resistance (MDR) pumps and is the primary cause of cancer's resistance to marketed drugs such as taxanes and vinca alkaloids. Azixa showed similar anti-cancer activity against both the resistant and non-resistant cell lines tested, demonstrating that the drug candidates are not substrates for MDR pumps [2].
Back to top
Recent Presentations on Azixa (verubulin, MPC-6827)
Back to top
References
- MPC-6827, a Small Molecule Inhibitor of Microtubule Formation with High Brain Penetration: Absorption, Distribution, Metabolism, Excretion, and Clinical Considerations. 96th Annual Meeting of the American Association for Cancer Research (AACR), 2005 in Anaheim, California. Poster PDF
- MPC-6827: A small molecule inhibitor of microtubule formation that is not a substrate for multi-drug resistance pumps. 96th Annual Meeting of the American Association for Cancer Research (AACR), 2005 in Anaheim, California.
Poster PDF
- MPC-6827, A Small Molecule Inhibitor of Microtubule Formation; Pharmacokinetics in Nu/+ Mice, Sprague Dawley Rats and Beagle Dogs Following Intravenous Administration. 96th Annual Meeting of the American Association for Cancer Research (AACR), 2005 in Anaheim, California.
Poster PDF
- Antitumor Activity of MPC-6827 in Human Breast, Colon, Pancreatic, Ovarian and Mouse Melanoma Tumor Xenografts in Athymic Nude Mice. The 95th meeting of the American Association for Cancer Research (AACR), March 27-31, 2004 in Orlando, Florida.Poster PDF
- Vascular Disruption Effects of MPC-6827. 98th Annual Meeting of the American Association for Cancer Research (AACR), 2007 in Los Angeles, California. Poster PDF
- Two phase 1 studies of MPC-6827, a novel vascular disrupting agent (VDA), in patients with advanced solid tumors and CNS metastases. 43rd Annual Meeting of the American Society of Clinical Oncology (ASCO), 2007 in Chicago, Illinois. Poster PDF
|
Information for Clinicians
