biOasis to file IND for HER2+ brain cancer treatment in 2016
biOasis (OTCQX:BIOAF; TSX-V:BTI) hopes to file an Investigational New Drug application with the FDA next year to begin human testing of its Transcend platform against HER2 positive brain tumors, which result from HER2+ breast cancer metastasizing to the brain.
“Given the significant unmet medical need of this condition, we are in discussions for a possible Phase 1 of a Phase 1/2b clinical trial in the U.S.,” CEO, Rob Hutchison, says in an interview with BioTuesdays.com.
“We have also had some partnering discussions with European companies interested in our program as well as academic institutions in the U.S., but right now, we are prepared to advance this program ourselves,” he adds.
Mr. Hutchison explains that biOasis’ Transcend platform represents a naturally occurring physiological solution to the delivery of therapeutics to the brain.
The platform is based on the human protein, melanotransferrin (MTf), and a small peptide (MTfp) within the protein as carriers to deliver therapeutics across the blood-brain-barrier (BBB) for the treatment of CNS diseases. MTfp consists of less than 20 amino acids and is less than 2/100th the size of the full protein.
The BBB is a dense, 400-mile network of capillaries that separate the brain from the circulatory system. Its purpose is to block harmful chemicals from entering brain tissue.
The problem, however, is that the BBB also prevents anti-cancer drugs, enzymes, antibodies, and gene silencing (siRNA) therapy from entering the brain at levels effective for treatment. The BBB blocks about 98% of small molecule drugs and 100% of large molecular drugs.
Mr. Hutchison refers to MTfp as “our secret sauce.” It has shown improved brain penetration and has greater commercial potential than the full-length MTf protein, he adds.
Other advantages of the peptide are a lower cost of production, improved quality control and greater consistency in manufacturing, he adds. MTfp is also simpler for chemists to link to medicines and it can transport a variety of compounds, with no apparent size limitation, across the BBB.
“Our R&D is now focused around MTfp as opposed to the full length protein,” he says, adding that MTfp also extends the company’s patent portfolio. We can also design much more efficient fusion proteins with MTfp so it becomes easier to manage, with more consistency batch-to-batch.”
Doug Loe, an analyst with Euro Pacific Canada, says there is nothing trivial about getting molecules across the BBB. “I have a positive view of Transcend. It is a broadly active platform for which proof-of-concept has been demonstrated and the preclinical data are as good as they can be at this point.”
biOasis’ lead program is Transcend plus trastuzumab, or MTfp-TZM. Trastuzumab is the active ingredient in Herceptin, a humanized monoclonal antibody used to treat HER2+ breast cancer.
Mr. Hutchison points out that Herceptin significantly increases survival rates in breast cancer patients but about 40% of patients eventually develop breast cancer metastasis in the brain. And Herceptin does not cross the BBB on its own.
In earlier animal studies conducted at Texas Tech University, Transcend plus trastuzumab reduced the number of HER2+ breast cancer tumors in the brain by 68%, with total tumor volume reduced by 84% in 14 days after four treatments.
In addition, the treatments increased the cancer killing effect of Herceptin in tumors throughout the body when linked with MTf, he adds.
“Our technology offers the potential to be used in conjunction with HER2+ cancer therapy as a treatment and preventative measure before the cancer metastasizes to the brain.”
According to Mr. Hutchison, the company has not seen any neuro-toxicology issues in its Transcend studies but expects to conduct a small animal toxicology workup before it files its IND next year.
“When we started our program in 2011, about 30% of HER2+ breast cancer patients developed metastases in the brain. But Herceptin does such a great job at the primary cancer site that brain tumors in these patients have now climbed to 40%,” he points out.
Mr. Loe says the melanotransferrin platform seems to work when linked with a therapeutic, elevating brain levels substantially higher than the therapeutic can reach on its own. “Herceptin is one of several candidates where biOasis has demonstrated that to be the case.”
Besides Herceptin, other blockbuster cancer drugs that frequently metastasize in the brain include Rituxan, which is used to treat blood cancers such as lymphoma and leukemia, and Erbitux, which is used in patients with lung and colon cancers.
Beyond metastasized brain cancer and glioblastoma, Mr. Hutchison suggests that the Transcend drug delivery platform can offer potential treatments for neurodegenerative diseases such as Alzheimer’s disease, stroke and traumatic brain injury, metabolic diseases such as lysosomal storage disease and gene silencing therapy.
“These are all multibillion-dollar markets and a carrier to cross the BBB would establish a foothold in these major markets,” he contends.
Mr. Hutchison says another area of significant interest to biOasis is lysosomal storage disease, such as Hunter syndrome, a rare inherited condition, which primarily affects children. Hunter is caused by a deficiency of the enzyme, IDS (iduronate-2-sulfatase).
Preclinical studies demonstrated that Transcend plus an IDS conjugate increased IDS brain enzyme activity by about 20 fold, offering the potential of an efficient enzyme replacement therapy, he adds.
The company also has generated positive delivery to the brain in another lysosomal storage disease, Hurler Syndrome, with a Transcend plus IDU (alpha-L-iduronidase) conjugate. Hurler is caused by an IDU deficiency in the brain.
In March, biOasis announced the results of an ischemic stroke model performed using the Transcend peptide carrier, MTfp, coupled to a siRNA. In the study, the company demonstrated that the MTfp-siRNA therapeutic was successfully transported across the BBB, reduced the volume of the brain infarct, and improved overall brain function as determined by neurological scoring.
“It’s one thing to say we crossed the BBB, but the significance of this stroke model was that we delivered a therapeutic level of siRNA and reduced the area of infarct, aiding in the recovery of the animals,” Mr. Hutchison contends.
biOasis hopes the efficacy study will support licensing MTfp to interested gene therapy companies for the treatment of CNS diseases such as Parkinson’s disease and ALS, he adds.
According to Mr. Hutchison, studies conducted by biOasis’ licensing partner, MedImmune, have produced data that illustrate certain desirable characteristics of MTfp.
To validate a peptide-licensing model, MedImmune was provided with the amino acid sequence of MTfp. Using the MTfp sequence, MedImmune designed and manufactured a fusion protein comprised of MTfp coupled to an antibody that targets a pain receptor in the brain.
In an animal model, the fusion successfully crossed the BBB and also showed pain reduction equal to or better than the currently used therapeutic.
“These results with MedImmune are of great importance for biOasis and its licensing business model,” Mr. Hutchison says.
“We now know that the MTfp amino acid sequence can be provided to a licensee and the licensee will be able to build the sequence into its therapeutics with relative ease and with low manufacturing costs,” he adds.
“In addition, the increased half-life observed with the MTfp transport vector results in a much higher exposure of the therapeutic in the brain, a key consideration for our potential licensing partners.”