Technology proof-of-concept

With the G-technology^® [liposomes coated with glutathione-conjugated polyethylene glycol (PEG)], to-BBB has shown that it is possible to considerably enhance the delivery of free drug compound across the blood-brain barrier. Liposomal formulation allows a wide range of compounds, like small molecules, antibodies, enzymes and RNA to be encapsulated without changing their function and protecting them against degradation and immune responses. Coating of liposomes with PEG will ensure a prolonged circulation time in plasma, where conjugation of glutathione to the tips of the PEG molecules will target the liposomes towards the active glutathione transporters on the blood-brain barrier.

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.

2B3-101: to-BBB's lead compound

Based on previous validation results obtained with the G-Technology^®
platform, to-BBB is developing several internal products. Currently, to-BBB’s lead compound involves doxorubicin glutathione-PEG liposomes. Doxorubicin is a conventional anthracycline that, either as free drug or encapsulated in (PEGylated) liposomes, 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.

Based on the existing clinical data of doxorubicin PEG-liposomes (Doxil/Caelyx) in brain cancer, the use of glutathione as food supplement or supportive therapy in chemotherapy, as well as the validation of the G-technology in a range of disease models, to-BBB has decided to develop proprietary doxorubicin glutathione-PEG liposomes (2B3-101) for enhanced delivery of doxorubicin to brain cancer. The product can be developed for multiple brain cancer indications and to-BBB considers development for brain metastases of breast cancer as well as glioma. Several proof of concept studies performed by The Netherlands Cancer Institute- Antoni van Leeuwenhoek Hospital (NKI-AVL) have shown a reduced brain tumor growth and a prolonged survival by 2B3-101. Formal preclinical development has been done with scaled-up (pre-)clinical material provided by manufacturer partner TTY Biopharm. GLP toxicity studies with 2B3-101 are showing a solid and predictable safety profile and will be completed mid 2010. Based on this preclinical data package to-BBB expects to initiate a Phase I/II clinical trial around the end of 2010. The clinical development plan has been validated through input of leading oncology experts and scientific advice from the Dutch and Swedish regulatory authorities. In June 2010 the Committee for Orphan Medical Products (COMP) granted Orphan Drug Designation for 2B3-101 in glioma.

Pipeline

Based on the additionally available proof-of-concept animal data using the G-Technology^® with anti-cancer drugs and analgesic peptides, to-BBB is considering the development of other product candidates in the disease areas of Alzheimer’s Disease, Multiple Sclerosis, Lysosomal Storage Diseases, Parkinson’s Disease and ALS. In addition to the internal development, to-BBB has several partnered projects on brain-delivery of compounds with (bio)pharmaceutical companies.