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Azixa™ (MPC-6827)
Azixa (MPC-6827) is an investigational new cancer drug being developed by Myriad Pharmaceuticals for the treatment of advanced primary and metastatic tumors.
About Azixa (MPC-6827)
 Azixa (MPC-6827) is a novel small molecule inhibitor of microtubule formation [1] that has demonstrated the ability to inhibit tumor growth in nonclinical testing, with activity in animal models of human melanoma and cancers of the ovary, breast, prostate, colon and pancreas [4]. In nonclinical testing, Azixa has been equally active against multiple drug resistant cancers as with susceptible tumors [2], unlike many of the current options in cancer chemotherapy, a limitation that represents a significant unmet medical need.
In mice, the pharmacokinetics of Azixa indicated that the drug distributed rapidly into the brain . The concentration of Azixa in brain tissue was approximately 14 times higher than the plasma concentration and was easily exceeds in vivo the concentration required to activate caspase and induce the cancer cell killing apoptosis process in cancer cells in vitro [1,3]. Importantly, Azixa was cleared from the brain at a rate similar to that observed from blood [3]. This suggests a special opportunity to study anti-tumor activity in patients with primary brain tumors and brain metastases that currently cannot be treated effectively with chemotherapy due to ineffective drug penetration into the brain.
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Mechanism of Action
Azixa has a dual mode of action; it acts as a cytotoxin [1] and a vascular disrupting agent (VDA) [6]. Mechanism of action studies have shown that, in vitro, Azixa binds to the same or nearby site on ß tubulin as colchicine, and inhibits microtubule assembly [1]. This inhibition of microtubule formation interferes with the transition through the G2/M phase of the cell cycle and leads to mitotic arrest and cell death [1]. In addition, as a VDA , Azixa kills tumor cells by reducing the blood supply to the tumor [2]. The disruption of the tumor vasculature results in acute ischemia followed by massive tumor cell death. Azixa is believed to selectively disrupt tumor vasculature and not established vasculature in healthy tissue by inhibiting the formation of microtubules. Tumors rely on microtubules to maintain the cytoskeletal structure of their new vasculature, whereas mature vascular endothelium of healthy tissue uses actin filaments to provide the needed structure.
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Nonclinical Studies
Myriad tested Azixa against pancreatic tumors in a mouse xenograft model to mimic the human form of the disease [4]. At a significantly lower dose level, Azixa was twice as active as gemcitabine, the standard of care in pancreatic cancer, in inhibiting tumor growth [4]. In further nonclinical testing, Azixa demonstrated a substantial inhibition of prostate cancer tumor growth, for which there is no currently recognized standard of care [4].
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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 paclitaxel and vinblastine. 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.
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About Metastatic Brain Cancer and Melanoma
There are approximately 170,000 new cases of metastatic brain tumors in the United States each year, and this number has risen steadily as survival from the originating primary tumors has improved. Brain metastases account for 20% of all cancer deaths each year in the United States. Patients with metastatic brain tumors have very limited options for treatment. Survival after a brain tumor diagnosis is typically short depending on the tumor status and treatment options. The standard of care for these patients is primarily surgery and whole brain radiation.
There are expected to be approximately 62,000 Americans diagnosed with melanoma this year. About half of all patients with melanoma will have brain metastases. Unfortunately, once a tumor of melanoma origin has been found in the brain, median survival is only three months. Most anticancer drugs are unable to cross the blood/brain barrier in sufficient concentration to achieve clinical benefit to the patient. There is currently no approved chemotherapy for metastatic brain cancer.
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About GBM Brain Cancer
There are approximately 18,000 primary brain tumors diagnosed in the United States each year. Glioblastoma multiforme (GBM) is by far the most common and most aggressive primary brain tumor. The standard of care for patients with GBM is primarily surgery and whole brain radiation. The 5 year survival rate of the disease has remained unchanged over the past 30 years, and stands at less than three percent. Even with complete surgical resection of the tumor, combined with the best available treatment, the survival rate for GBM remains very low. Most anticancer drugs are unable to cross the blood/brain barrier in sufficient concentration to achieve clinical benefit to the patient.
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About Non-Small-Cell Lung Cancer
According to the American Cancer Society, there are expected to be approximately 185,000 Americans diagnosed with non-small-cell lung cancer this year. About 80% of all patients with non-small-cell lung cancer who survive for more than two years, will have brain metastases. This is in part because most anticancer drugs are unable to cross the blood/brain barrier in sufficient concentration to achieve clinical benefit to the patient. The use of such chemotherapeutic agents can transiently weaken the blood-brain barrier and allow systemic disease to be seeded in the brain, leaving the brain susceptible to tumor growth. Once a tumor of non-small-cell lung cancer origin has been found in the brain, median survival is generally reported as just three to six months. There is currently no FDA-approved chemotherapy for metastatic brain cancer.
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Clinical Trials
Azixa (MPC-6827) is currently being evaluated in three Phase 2 human clinical trials, one in patients with primary brain cancer, one in melanoma that has spread to the brain, and one in patients with non-small-cell lung cancer that has spread to the brain.
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Recent Presentations on Azixa
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]
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Azixa is a novel small molecule inhibitor of microtubule formation that has shown evidence of tumor vascular disruption.  |
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