R&D

GRN1005 – An LRP-directed peptide-drug conjugate against cancer in the brain

The blood-brain barrier (BBB) prevents most drugs, including oncology drugs, from entering the brain. This presents a practical challenge to the treatment of both primary brain tumors and brain metastases, which represent a substantial global unmet medical need. Metastases in the brain arising from primary tumors in other organs are associated with considerable morbidity and mortality, and there are currently no drugs approved for brain metastases. Transport of effective anti-cancer agents across the BBB and into the tumor is critical for developing effective treatments for cancer in the brain.

About GRN1005

GRN1005 is an LRP-directed peptide-drug conjugate that is being developed for the treatment of tumors in the brain, including malignant glioma and brain metastases from solid tumors. GRN1005 is designed to deliver cytotoxic drug across the BBB and into tumors by exploiting a native transport mechanism by which essential substances, such as lipids and hormones, successfully enter the brain through receptors. GRN1005 is comprised of three molecules of paclitaxel, linked to a proprietary peptide that is designed to target the lipoprotein receptor-related protein-1 (LRP-1), one of the most highly expressed receptors on the surface of the BBB. Binding to LRP-1 facilitates receptor-mediated transport, or transcytosis, across the BBB into the brain tissue. LRP-1 is also up-regulated in many tumors; therefore, once in the brain GRN1005 may gain entry into tumor cells using the same receptor by a process known as endocytosis. GRN1005 is a prodrug, which becomes activated in cells only after it is cleaved by esterases to release active paclitaxel from the peptide.

GRN1005 was in-licensed from Angiochem, Inc.

Phase 1 Clinical Results

GRN1005 was evaluated in two Phase 1 clinical trials treating a total of 119 patients to identify the maximum tolerated dose (MTD) and obtain data on safety, tolerability and preliminary evidence of efficacy in patients with advanced solid tumors with brain metastases and in patients with recurrent malignant glioma. Results from the trials include:

• Overall response rate in patients with advanced solid tumors with brain metastases treated at the MTD was 20% (4/20), including patients who had previously progressed on taxane therapy. Activity against tumors was observed inside and outside of the brain.
• Response rate in patients with recurrent malignant glioma treated at MTD was 6% (1/17).
• Concentrations of GRN1005, well above those required for cytotoxicity, were detected in primary brain tumor samples taken from patients who had received a single dose of the drug prior to undergoing debulking surgery, indicating that the drug successfully crossed the BBB and entered the tumor.
• Concentrations of GRN1005 in the plasma were found to be several times higher than had been previously demonstrated with free paclitaxel.
• Toxicity was similar in nature to paclitaxel, with dose-limiting toxicity due to neutropenia, which was manageable. No CNS toxicity was observed in patients assessed by neurocognitive testing.

Final data from the Phase 1 clinical trials with GRN1005 were presented at the November 2011 AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics.

Phase 2 Clinical Program

Based on compelling results obtained in the Phase 1 clinical trials, we have progressed to evaluate GRN1005 in two Phase 2 clinical trials in patients with cancer that has metastasized to the brain.

The objective of our Phase 2 program with GRN1005 is to confirm the clinical activity observed in the Phase 1 study in brain metastases. We anticipate obtaining top-line data by the middle of 2013 to enable a decision regarding further development.

Related Presentations

• AACR-NCI-EORTC 2011