Azixa (MPC-6827) is an investigational new cancer drug being developed by Myriad Pharmaceuticals for the treatment of advanced primary and metastatic tumors.

Page Contents

• About Azixa (MPC-6827)
• Preclinical Studies
• About Metastatic Brain Cancer and Melanoma
• About Multiple Drug Resistance
• About GBM Brain Cancer
• Clinical Trials
• Recent Presentations
• References

About Azixa (MPC-6827)

Azixa is our most advanced cancer drug candidate and is being developed 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 [3] [7]. 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 subject to multiple drug resistance [2]. Azixa is currently being tested in clinical studies in patients with glioblastoma multiforme and metastatic melanoma.

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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 [3] [7]. 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 [3] [7]. 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 cytotoxic chemotherapies or as a single agent [5]. In addition, data from two xenograft cancer models demonstrated that the combination of Azixa and Avastin® (bevacizumab) was more efficacious than treatment with Avastin alone [9].

The distribution of Azixa into the CNS was evaluated in mice and the time to maximum drug concentration was the same in both 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 [8] [9].

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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 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 [3] [7].

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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 systemic therapy for solid tumors has advanced. 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 as most therapies do not cross the blood-brain-barrier. Survival after metastatic brain disease is typically short, depending on the extent of the tumor involvement elsewhere in the body and the available treatment options.

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. There is currently no approved chemotherapy for metastatic brain disease or for metastatic melanoma with brain metastasis.

In a Phase 2 clinical trial, twenty-two patients with refractory metastatic melanoma have been studied at three different doses of Azixa [10]. The combination of Azixa at all concentrations with fixed dose temozolomide, including the previously determined single agent maximum tolerated dose of Azixa, was safe and well-tolerated. A dose reduction of Azixa was not required when combined with temozolomide in these patients. The median progression free survival of 2.8 months is favorable when compared with a randomized phase 3 study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma (1.9 and 1.5 months, respectively) [11]. Data collection and patient follow-up in this study are continuing.

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 long-term survival rate remains low. Most anticancer drugs do not cross the blood-brain-barrier in sufficient concentration to achieve clinical benefit.

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Clinical Trials

Azixa (MPC-6827) is currently being evaluated in three ongoing Phase 2 clinical trials. In one study three dose levels of Azixa are being administered with carboplatin to subjects with recurring/relapsing glioblastoma multiforme. In a second study, three dose levels of Azixa will be administered with temozolomide to subjects with metastatic melanoma. In the second quarter of 2009, we initiated an open label Phase 2 clinical trial to evaluate Azixa as monotherapy in recurrent glioblastoma multiforme.

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Recent Presentations on Azixa

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