Drug Delivery Technology Crosses Blood-Brain Barrier

Following successful preclinical studies, the technology is being evaluated in two phase I clinical trials in patients with malignant glioma and brain metastases.

The blood-brain barrier is formed by a network of closely sealed endothelial cells in the brain's capillaries, and it expresses a high level of proteins that drive foreign molecules away from the brain, while allowing others (such as glucose and insulin) that are needed for the functioning of the brain cells to cross the barrier. This makes it very difficult for molecules, including anti-cancer drugs, to cross the blood-brain barrier and reach tumor cells in the brain.

Currently, less than 5% of drugs (made up of very small molecules) are able to cross the barrier; one example is temozolomide, which is the only chemotherapy available for treating brain tumors such as glioblastoma multiforme and progressive anaplastic astrocytoma. These tumors have a poor prognosis and continue to grow, even after treatment with temozolomide. Therefore, new therapies for these hard-to-treat brain tumors are needed urgently.

In four related studies presented at the 20th EORTC- (European Organization for Research and Treatment of Cancer), [U.S.] NCI- (National Institute of Cancer), and AACR (American Association for Cancer Research) Symposium on Molecular Targets and Cancer Therapeutics in Geneva, Switzerland, on October 22, 2008, scientists from Canada, the United States, and France described how they are investigating a new drug delivery technology that provides a noninvasive and flexible way of transporting different drugs (for example, antibodies, proteins, peptides, siRNA, small molecules) across the blood-brain barrier and into the central nervous system.

The drug being evaluated in the four presentations is called ANG1005. It is comprised of one molecule of a peptide, called Angiopep-2, joined together with three molecules of paclitaxel, a taxane chemotherapy drug. Dr. Reinhard Gabathuler, author of one of the abstracts and chief scientific officer from Angiochem, Inc. (Montreal, QC, Canada), the company that is developing the Angiopep technology and ANG1005, explained, "Unlike invasive or pharmacological approaches to deliver drugs to the brain, the Angiopep technology utilizes the physiological approach by making use of the receptors on the surface of the blood-brain barrier that are responsible for actively transporting necessary molecules across the barrier to the brain. The family of Angiopeps (including Angiopep-2) has been designed to interact with a specific receptor, low-density lipoprotein receptor-related protein-1 [LRP-1]. This receptor has many functions, binds over 30 ligands [molecules] of various sizes, and is highly expressed at the blood-brain barrier.”

In laboratory-based tests of ANG1005 on mice and rats, Dr. Gabathuler, other scientists in the company, and collaborators in the United States and Canada found that the drug was transported rapidly across the blood-brain barrier and into the functional part of the brain, the parenchyma. "In contrast to free paclitaxel, which is normally prevented from reaching the brain by the P-glycoprotein efflux pump, ANG1005 is efficiently transported across the blood-brain barrier, with approximately 100-fold higher transport rate compared to free paclitaxel and 10-fold higher transport rate than temozolomide,” he said. Moreover, the drug resulted in a significant, 27% increase of survival of mice with glioblastoma tumors and a shrinking of glioblastoma tumors in rats.

A second study, led by Dr. Francis Bichat, head of the scientific platform at Oncodesign (Dijon, France), evaluated the anti-cancer properties of the drug in cancer cell lines and mice, further investigating its toxicity and what happened to the drug in mice. He discovered that ANG1005 had the same anti-cancer characteristics as did free paclitaxel (paclitaxel on its own) in cancer cell lines. Speaking before the conference, he said, "The anti-tumor activity of paclitaxel was maintained with ANG1005 compared with free paclitaxel. There was no loss of activity.” He also found a significant inhibition of brain tumor growth in rats when they were treated with ANG1005, whereas tumors in rats that were treated with paclitaxel did not have their growth inhibited.

"This is probably because free paclitaxel is not able to enter the brain,” Dr. Bichat said. "The most interesting finding from this study is the potency of ANG1005 to bypass the blood-brain barrier and to allow paclitaxel into the brain where it shows anti-tumor activity,” said Dr. Bichat.

The success of these pre-clinical studies enabled Angiochem to initiate two phase I clinical trials at cancer centers in the United States: one in patients with advanced cancer and brain metastases, and the second in patients with recurrent malignant glioma. These trials are still being conducted, but, as of September 23, 2008, 22 patients with advanced solid tumors (including breast cancer, melanoma, liver cancer, and 15 patients with brain metastases) have been treated with ANG1005 in the first trial. The drug is given by intravenous infusion for one hour, every 21 days. At doses up to 500 mg/m2 the drug appears to be safe and well-tolerated and no patient has discontinued due to adverse side-effects. The researchers are continuing to increase the dose.

Dr. Jean-Paul Castaigne, president and chief executive officer of Angiochem, who presented the clinical trials results, said, "To date, the safety and tolerability of ANG1005 has been excellent in patients with advanced solid tumors and brain metastases.”

In the second trial in patients with recurrent malignant glioma, 12 patients had been treated by September 23, 2008--eight with glioblastoma multiforme, one with anaplastic astrocytoma and three with anaplastic oligondendrocytoma. Dr. Castaigne said, "We have demonstrated that the drug is safe and tolerable up to and including doses of 75 mg/m2 and we are currently evaluating doses of 105 mg/m2. No patient has discontinued due to drug-related adverse side effects. So far, all patients [with the exception of one] dosed up to 50 mg/m2 have had their disease progress following two cycles of treatment at six weeks. However, it should be noted that 50 mg/m2 of ANG1005 has an equivalent paclitaxel dose of only about 25 mg/m2, which is still quite low for appreciable cytotoxic effects. To date, treatment options for patients with recurrent malignant glioma are limited and prognosis is bleak because of the brain's highly evolved physiologic structure. Results from both these trials show that Angiopep conjugates may provide a potentially safe and effective way to treat gliomas and other currently unmanageable diseases of the central nervous system. The Angiopep technology is well-tolerated, since most of the side-effects observed to date with ANG1005 are caused by paclitaxel, the active drug component.”

Both trials will be reporting their most important results by the end of 2008, and researchers are planning a continuation of the trial in patients with brain cancer in 2009.

Dr. Castaigne said, "Angiochem's intention is to continue the early development of ANG1005 until proof-of-efficacy is obtained in either progressive malignant gliomas or brain metastases. We will seek to find a partner with significant oncology experience to carry forward the later development stages and marketing of ANG1005. Although other technologies have demonstrated abilities to cross the blood-brain barrier, we believe that the Angiopep technology is the furthest developed of the physiological approach and has significant advantages. ANG1005 is the company's first compound in clinical development using the Angiopep technology. We have been successful in conjugating other chemotherapeutics [e.g., doxorubicin and etoposide] to our technology; preclinical data have demonstrated success in delivering these compounds into the brain and retaining cytotoxic activities. Angiochem is also focusing considerable effort on the conjugation and delivery of other drug classes [including monoclonal antibodies, proteins, peptides, siRNA] to treat other CNS [central nervous system] disorders.”

Related Links:
Angiochem
Oncodesign