GRN-1005, an LDL receptor-related protein 1-targeted paclitaxel conjugate for the potential intravenous treatment of primary and metastatic brain tumors

GRN-1005, being developed by Geron under license from AngioChem, is a peptide vector (called Angiopep-2) linked to three molecules of paclitaxel, for the potential intravenous treatment of primary and metastatic brain tumors. The peptide vector component of GRN-1005 was designed to optimize the crossing of the blood-brain barrier and the delivery and release of active drug. In vitro studies demonstrated that GRN-1005 has comparable activity to that of paclitaxel in different carcinoma cell lines, but with a relevant lower toxicity on endothelial cells. Using in vivo models of glioblastoma and NSCLC, relevant tumor growth inhibition was observed following GRN-1005 treatment. Furthermore, studies using MDR1A-deficient mice confirmed that GRN-1005 does not interact with P-glycoprotein. Data from phase I clinical trials in patients with primary or metastatic brain tumors demonstrated the potential efficacy of GRN-1005 for delaying tumor progression or causing tumor regression. The common adverse effects were related to paclitaxel toxicity and the MTD and recommended phase II dose of GRN-1005 was 650 mg/m2. At the time of publication, a phase II trial (NCT01480583) of GRN-1005 in combination with the anti-HER2 mAb trastuzumab in patients with HER2-positive metastatic breast cancer had recently been initiated.