Taking a ride across the BBB with biOasis
biOasis (OTCQX:BIOAF; TSX-V:BTI) believes its Transcend family of technologies holds the key to allow drug therapies to penetrate the blood-brain barrier (BBB) – long considered a Holy Grail of neurological medical research – to treat diseases of the central nervous system.
“Our Transcend breakthrough is a naturally occurring physiological transport mechanism that can act as a Trojan Horse to transport therapeutics across the BBB and into brain tissues,” chairman and CEO, Rob Hutchison, says in an interview with BioTuesdays.com.
Mr. Hutchison explains that the BBB is a tightly woven capillary network of endothelial cells lining blood vessels in the brain that prevents toxic compounds entering the brain from the circulatory system. This capillary network does not exist in normal circulation.
The BBB prevents 98% of small molecule drugs and 100% of large molecule drugs from entering the brain, he adds.
For example, a patient with a broken leg may be given a 2.5 mg dose of morphine for pain, but only a fraction of the drug crosses the BBB to reach pain receptors in the brain for pain relief.
While cancers originating in the brain are fewer than in other regions of the body, 10 times as many people develop brain tumors from cancers that metastasize elsewhere in the body.
Citing the research of biOasis’ founding scientist, Wilfred Jefferies of The University of British Columbia, Mr. Hutchison says that brain capillaries, which comprise the BBB, possess an endogenous receptor that ferries an iron-transport protein, called p97, or melanotransferrin, across the BBB.
p97 is found in low concentrations in the blood and represents biOasis’ first-generation Transcend technology.
“We call Transcend a family because we have recently discovered a new peptide within Transcend, called Transcendpep, which offers improved brain penetration over Transcend,” he contends.
Mr. Hutchison says the company has done a number of preclinical studies with its small peptide and found that it can piggyback a variety of compounds with no apparent size limitation and, in some cases, provide even better transport than p97 across the BBB.
“This represents a significant finding for the company,” he adds. “Transcendpep is our secret sauce.”
The Transcendpep technology has attracted the interest of a number of pharmaceutical collaborators to biOasis. “Essentially, we have the potential to add our transporter peptide to the chemical makeup of a drug so that the drug, in effect, becomes the active transporter across the BBB,” Mr. Hutchison points out.
A carrier across the BBB, with efficacious activity, would establish a foothold within many multibillion-dollar markets, including oncology, pain and migraine, neurodegenerative and infectious diseases, stroke and traumatic brain injury.
Independent studies have shown that, in terms of a rapid uptake in the brain, Transcend follows closely behind glucose but is well ahead of morphine and other compounds, including aprotinin and insulin receptor antibody.
biOasis has obtained third party validation of its technology from groups such as the National Research Council of Canada, BC Cancer Research Center and Texas Tech University Health Sciences Center. In addition, biOasis has secured more than 30 patents relating to the Transcend family for BBB delivery and neurodegenerative diseases.
According to Mr. Hutchison, biOasis has been able to link the Transcend family with antibodies, enzymes, biologics and small molecule drugs to target specific brain cells and intracellular compartments of the brain, such as lysosomes, endosomes and mitochondria.
“Essentially, we’ve shown that we can cross the BBB. Now, we have to show that we can deliver an efficacious amount of drug along with our Transcend technology.”
Noting that many companies are facing the end of patent protection for their blockbuster drugs, he says that the Transcend family, linked with certain existing drugs that are nearing the end of their patent life, offers the potential for patent term extensions through the development of new chemical entities.
In the case of Herceptin, which is widely used to treat HER2+ breast cancer and is coming off patent in Europe and is expected to lose patent protection in the U.S. in 2016, Mr. Hutchison notes that preclinical studies with Transcend and a Herceptin conjugate “not only crossed the BBB and also demonstrated increased cancer killing activities in general.”
While Herceptin alone has improved the outcome of HER2+ breast cancer patients, some 40% of patients develop metastasis in the brain and Herceptin does not cross the BBB.
In preclinical studies, a Transcend-Herceptin combination reduced the number of HER2+ breast cancer tumors in the brain by 68%, and the tumors that remained after treatment were 57% smaller.
Mr. Hutchison says biOasis is seeking patent protection around a Transcend-linked conjugate of Herceptin and plans to submit an IND in mid-2015 for human testing of the combination.
To date, biOasis has completed four strategic collaborations on its first-generation Transcend with Shire Human Genetic Therapies, AbbVie (NYSE:ABBV), MedImmune and UCB Pharmaceuticals. biOasis has inked a licensing agreement with MedImmune for its second-generation Transcendpep and is in talks with AbbVie and UCB.
Among biOasis’ external preclinical development programs, Mr. Hutchison says that Transcend, linked with an anti-amyloid beta antibody, demonstrated a fivefold increase of the combination into brain tissue, compared with the antibody itself, and potential as a therapeutic for reducing amyloid plaque of Alzheimer’s disease patients.
In Hurler Syndrome and Hunter Syndrome, two rare inherited diseases caused by an enzyme deficiency and occurring mainly in children, Mr. Hutchison says Transcend, combined with lysosomal enzymes, IDU and IDS, increased IDU and IDS enzyme activity in the brain by four times and 20 times, respectively. There is no cure for these lysosomal storage diseases.
Mr. Hutchison says the off-patent drug doxorubicin is now used as a treatment for several lymphomas and leukemias. While doxorubicin does not cross the BBB, there was a significant increase in brain uptake of a Transcend-doxorubicin conjugate, compared with the drug alone, he adds.
However, a serious side effect of doxorubicin is heart damage. Mr. Hutchison says there was a significant decrease in uptake of the Transcend-doxorubicin combination in the heart, compared with doxorubicin alone.
Working through the National Research Council of Canada, biOasis also has successfully delivered small interfering RNA to the brain via Transcendpep. Mr. Hutchison says this preclinical work foreshadows the potential for gene therapy to treat a variety of neurodegenerative disease such as Alzheimer’s, ALS and Parkinson’s, to name a few.