Motexafin Gadolinium
Cancer Treatment product candidate
Motexafin gadolinium (MGd) is a small-molecule drug with a novel mechanism of action; it accumulates selectively in cancer cells due to their increased rates of metabolism. Once inside the cell, MGd induces apoptosis (programmed cell death) by disrupting redox-dependent pathways. MGd inhibits the enzyme thioredoxin reductase, which is a tumor growth promoter. This mechanism provides the opportunity to use MGd in a wide range of cancers. MGd is paramagnetic, and therefore is detectable by magnetic resonance imaging (MRI), allowing the visualization of the drug in tumors.
"Pharmacyclics is planning to design and conduct a pivotal Phase 3 trial with MGd in patients with brain metastases from non-small cell lung cancer receiving whole brain radiation and stereotactic radiosurgery. This trial is anticipated to begin in the first half of 2009."
MGd in Brain Metastases
In an international randomized Phase 3 trial known as the SMART trial (Study of Neurologic Progression with Motexafin Gadolinium and Radiation Therapy), investigators found that patients (n = 551) with brain metastases from non-small cell lung cancer (NSCLC) given MGd in addition to whole brain radiation therapy (WBRT) had a median time to neurological progression of 15.4 months, compared to 10.0 months for patients who received only WBRT (P = 0.12, hazard ratio = 0.78), a trend in favor of the MGd-treated arm. In patients in North America, where radiation is prescribed promptly after diagnosis of brain metastases, the median time to disease progression was 24.2 months for patients receiving MGd + WBRT compared to 8.8 months for patients treated with WBRT alone (p = 0.004). The conclusion of this study was that MGd significantly prolonged time to neurologic progression in lung cancer patients with brain metastases receiving prompt WBRT. The results are published in the International Journal of Radiation Oncology.
An NDA for MGd was filed in April of 2007. In December 2007, the Company received a non-approvable letter from the U.S. Food and Drug Administration’s (FDA) Division of Drug Oncology Products regarding marketing clearance for MGd in combination with radiation therapy for the treatment of brain metastases from NSCLC.
MGd Used with Stereotactic Radiosurgery
A Phase 2 clinical trial of MGd plus stereotactic radiosurgery has been completed and the results were presented at the 2007 ASCO Meeting. The trial evaluated the safety, radiologic response and time to neurologic progression in 45 patients. Patients with brain metastases from cancers of the lung, breast and other cancers were treated with MGd plus WBRT, followed by stereotactic radiosurgery boost therapy to tumor sites in the brain. The results indicated that MGd may improve the efficacy of stereotactic radiosurgery by providing more accurate magnetic resonance imaging (MRI) treatment-planning and better defining the treatment field in patients with brain metastases from solid tumors. MGd allowed physicians to identify occult brain metastases in 24 percent of patients that were missed with standard MRI contrast agents, and were amenable to stereotactic radiosurgery.
MGd has been evaluated in clinical trials involving over 1000 patients and has been found to be generally well-tolerated, without the usual side-effects seen with standard chemotherapy. Its non-overlapping toxicity with chemotherapy and radiation therapy makes it potentially suitable for use in combination treatment regimens. Single-agent trials conducted to date have demonstrated anti-tumor activity in NSCLC, hematologic malignancies and renal cell cancer.
- Learn More – Understanding Brain Metastases