Beating the barrier

Life-saving disease modifying drugs are prevented from entering the brain by the neuroprotective blood-brain barrier – Willem van Weperen and Pieter Gaillard take a look at how to safely enhance drug delivery to the brain

The Central Nervous System (CNS) market has become one of the largest and fastest growing markets in the pharmaceutical industry. In 2007, it stood at $109b with a large number of diseases – brain cancer, Alzheimer’s disease, lysosomal storage diseases or Multiple Sclerosis – currently untreated or under-treated¹. As life expectancy increases, the incidence of CNS disorders, like Alzheimer’s disease, will increase further. Currently, CNS disorders represent 11% of the global burden of disease; in 2010 this is expected to rise to 14%, predominantly driven by the increasing life expectancy². Traditional small molecules will not be able to address these diseases adequately and more complex small molecules and biologics are needed to achieve disease modification.

The difficulty of treating CNS-related diseases is that potential life-saving drugs are prevented from entering the brain by the human blood-brain barrier. This sophisticated cellular barrier can be compared with a biological firewall, which protects the brain and maintains homeostasis. But since it also keeps out most therapeutic compounds there is unprecedented demand for new methods to safely deliver these potential new drugs into the brain. Currently, there are only a few approaches for brain drug delivery; these are limited in their application, and are highly invasive or disruptive to the neuroprotective blood-brain barrier^3,4,5.

The blood-brain barrier regulates and maintains brain homeostasis. It constitutes a physical barrier in the wall of the blood vessels inside the brain, which serves to protect neurons, just like a firewall protects a computer from potentially harmful intruders from the Internet. Additionally, the blood-brain barrier is a functional barrier, as it actively excludes, effluxes and metabolises potential neurotoxic compounds (including plasma proteins, cytokines, antibodies, drugs, bacteria and viruses). But normal brain function also requires a delicate ion, neurotransmitter and nutrient balance, therefore, the blood-brain barrier additionally orchestrates the selective uptake of life-essential nutrients and metabolites from the systemic circulation into the brain.

Biotechnology company to-BBB say they have found a safe proprietary brain drug delivery platform to help overcome the blood-brain barrier. This G-Technology, discovered by the Industrial Technology Research Institute (ITRI) in Taiwan, is the company’s core platform and uses liposomes coated with the tripeptide glutathione at the tips of polyethylene glycol (PEG) to safely enhance the delivery of free drugs to the brain. Intravenous injections of PEGylated liposomes are already on the market (e.g. Doxil/Caelyx), and high dosages of glutathione is supportive therapy in cancer.

Glutathione, a natural anti-oxidant, is found at high levels in the brain and its receptor is abundantly expressed at the blood-brain barrier. Therefore, glutathione uniquely minimises common risks like adverse immunological reactions or interference with life-essential physiologic pathways. Proof-of-concept studies with peptides and small molecules in pain, brain tumours and viral encephalitis demonstrated that the G-Technology is effectively and safely enhancing the delivery of drugs to the brain. Furthermore, a technological and mechanistic validation has shown that the higher the amount of glutathione coating of the brain-targeted liposomes, the more free drug was actually delivered to the brain⁶.

Next to safety and efficacy a major advantage of the G-Technology is the ability to include a wide range of molecules into the liposomes, which provides us with clear platform capabilities for brain delivery. The biggest advantage is that these molecules do not need to be chemically modified to be incorporated into the liposomes. This will ensure that the efficacy and safety profile is not changed. Furthermore, the liposomes have a long half-life in plasma (in the range of several hours or even several days in humans), and thus a large and long availability of the molecule to be delivered to the brain. Finally, glutathione as a targeting ligand can be used from mouse to men, enabling us to readily move forward from pre-clinical to clinical research.

Brain cancer affects up to 200,000 patients annually in the United States and similar numbers in Europe. Treatment options for this devastating disease are limited and overall prognoses are poor. Doxorubicin is a conventional anthracycline that – either as free drugs or encapsulated in (PEGylated) liposomes (Myocet or Doxil/Caelyx) – is widely used as anticancer treatment. However, these doxorubicin formulations do not effectively cross the blood-brain barrier to exert an effect in the brain. In collaboration with scientists of the Netherlands Cancer Institute, to-BBB has shown that doxorubicin glutathione-PEG liposomes significantly impact brain tumour growth and survival in proof-of-concept studies, which provides a strong basis for clinical development. Based on the strong potency of doxorubicin this is also a potential product for other brain cancer indications like glioblastoma, primary CNS lymphoma, medullablastoma, and brain metastases of small cell lung carcinoma. In addition, to-BBB also demonstrated a similar efficacy in systemic breast cancer and a similar safety profile of 2B3-101 compared to Doxil/Caelyx. These data imply a high likelihood of successfully developing a proprietary improved version of Doxil/Caelyx in systemic breast cancer with additional efficacy on brain metastases. With increasing diagnostic possibilities to predict the development of breast cancer (including brain metastases), this also provides a long-term perspective on preventive therapy for brain metastases before micro-metastases become symptomatic.

to-BBB has obtained scientific advice from European Regulatory authorities for the clinical development of this lead product 2B3-101 for brain metastases of breast cancer. For the development of 2B3-101, to-BBB obtained clinical scale batches of the brain-targeted doxorubicin liposomes, produced according to cGMP standards by TTY Biopharm from Taiwan. 2B3-101 is planned to be in phase I/II towards the end of 2010.

In conclusion, the G-Technology obtained proof-of-concept by using peptides and small molecules in cell-based assays and animal models for brain cancer, pain and viral encephalitis. Furthermore, a technologic and mechanistic validation assay has shown that the free drug was delivered to the extracellular fluid of the brain and that an apparent maximum of 500% of that of PEG liposomes was reached using glutathione-PEG liposomes with optimal glutathione coating. Although the ultimate brain uptake and efficacy of any encapsulated compound will depend on the compound as well as the disease, to-BBB will be able to test and optimize the G-Technology for almost every specific situation.