BriaVax™ Phase 1/2 Clinical Trial To Start Shortly
Earlier this week the company announced it is planning to initiate a Phase 1/2 study with BriaVax™ in the second quarter 2016. The trial is expected to enroll up to 24 late-stage cancer patients, mostly with metastatic breast cancer, although some patients with late-stage lung or ovarian cancer may also enroll in the study. Enrollment is expected to take place at several university hospitals in the U.S. Management is currently working to finalize the protocol and expects to provide an update on the final design in the coming weeks; however, my guess is that the first portion of the trial will enroll 8-10 patients with an interim safety and efficacy read-out ahead of expansion to the Phase 2 portion.
BriaCell is also working to finalize an agreement with a contract research organization (CRO) to conduct the planned trial. The company began engaging with various CRO's when the FDA cleared the U.S. investigational new drug (IND) application in November 2015. A final CRO selection announcement is imminent. Additionally, the company also reported that manufacturing of BriaVax™ is nearing completion at the company's partner, University of California Davis. UC Davis is manufacturing compliant cGMP-grade BriaVax™ to be used in dosing patients during the upcoming Phase 1/2 trial, with several BriaVax™ batches already completed.
I'm expecting enrollment to begin in June or July 2016. As noted above, the initial portion of the trial will likely involve enrollment of 8-10 patients with an interim analysis at 4-6 months. Based on what I have seen in the past, the Phase 1 portion of the trial will likely cost $0.5 million (best guess is $2-3 million for the full trial all-in). I think BriaCell will look to get the trial underway with existing funding or a small bridge financing, saving a potential larger financing until after the interim update.
Quick Background On BriaVax™
BriaVax™ is a proprietary whole tumor cell vaccine isolated from a chest wall lesion of a 39-year-old woman with metastatic breast cancer. The irradiated cells are ER/PR negative and overexpress HER-2/neu, a clinically validated target of effective monoclonal antibody therapeutics. BriaVax™ has been genetically engineered to release sargramostim (granulocyte macrophage - colony-stimulating factor [GM-CSF]) for up-regulation of professional antigen-presenting cells. GM-CSF has been shown to be the most potent immunostimulatory secreted molecule for inducing tumor immunity (1) and is believed to provide an antitumor effect that prolongs survival and disease-free survival in subjects with stage III and IV melanoma (2) and metastatic non-small cell lung cancer (3). Also, part of the treatment regimen is the addition of low-dose cyclophosphamide (CY) 2-3 days prior to inoculation to down-regulate the activity of regulatory T cells and the use of interferon (IFN) alpha to boost differentiation of dendritic cells.Treatment with BriaVax™ is the result of decades of clinical investigation and research into therapeutic cancer vaccines and the use of an allogeneic whole cell breast tumor line that overexpresses a clinically validated tumor antigen in HER-2/neu. The cells have been genetically engineered to secrete GM-CSF, which has multiple effects on the tumor-immune response equilibrium, including activating dendritic cell recruitment and maturation. The protocol employs a novel use of CY to take the "foot off the brake" with respect to regulatory T cell response and then follows with a local injection of IFN-alpha to "step on the gas" and evoke prolonged immune response.
Targeted Approach Will Really Drive Interest In BriaVax™
What I find most interesting about BriaVax™ is the potential for a broad-spectrum targeted approach to immunotherapy. These two terms, broad-spectrum and targeting approach, seem contradictory to each other, as pharmaceutical products are usually either broad-spectrum (think chemotherapy) or targeted (think trastuzumab).
BriaVax™ is interesting because the administration of a genetically engineered whole tumor cell vaccine has the potential to present multiple tumor-specific antigens to the immune system, stimulating dendritic cells and inducing a humoral response magnified by the presence of GM-CSF. Additionally, the intravenous delivery of CY and injection of INF-alpha into the inoculation site induces a systemic immune reaction to intensify the effects of the drug. This is as broad-spectrum as they come.
However, recent news out of the company notes that BriaCell has identified a specific gene signature indicative of an exceptional response to BriaVax™ in previous clinical work. For example, in the company's previous Phase 1 trial, one patient demonstrated near complete remission of multiple breast cancer lesions after only three inoculations with BriaVax™. The patient then relapsed after the trial ended, at which time BriaCell approached the U.S. FDA about compassionate use of the vaccine for the patient. Upon subsequent retreatment (three additional rounds of BriaVax™), the patient demonstrated prompt tumor regression.
Read more about the results from this exception case study here >> BCT-P1 CaseStudy
BriaCell believes it has now identified a coherent set of biomarkers and gene signatures that allow the company to better understand how the BriaVax™ mechanism of action works. For example, BriaVax™ expresses several known cancer antigens, exerting its therapeutic effects via multiple modalities. The patient in the case study noted above was shown to express blood-derived cells complementing the gene expression signature of the vaccine.
Additional data on this specific targeted approach will be made available at the Annual Meeting of the American Association for Cancer Research (AACR) in two weeks. The company has submitted an abstract (AACR#2369) and will be presenting the data on April 18, 2016. What has been disclosed so far is that treatment with BriaVax™ results in a gene expression signature consistent with a mechanism of action involving not only the activation of cytotoxic T cells but also the induction of a humoral (antibody-mediated) response.
In the simplest terms, BriaVax™ looks to be acting as an antigen presenting cell and variation in major histocompatibility complex (MHC1 and MHC2) proteins seems to play a role in therapeutic effect. As such, identifying patients that express immunogens overexpressed in BriaVax™ compared to normal breast cells potentially explains the mechanism of action and encouraging clinical response observed thus far in Phase 1 studies. This is critical to the development of a diagnostic, BriaDx™, which will be used to better identify and target patients for the upcoming clinical program with the vaccine.
BriaCell Therapeutics remains one of my favorite under-the-radar immuno-oncology names. Therapeutic cancer vaccines have a lamentable history (4), but the science has come a long way since the failures of Dendreon's Provenge®. BriaVax™ is an allogeneic whole cell vaccine, and thus not hampered by the immune masking or the commercial logistical nightmares of previous autologous approaches. Instead, BriaVax™ seems to offer the ideal immunotherapy - powerful enough to induce both a broad-scale innate and adaptive immune reaction but targeted to reduce systemic side-effects and improve the odds of tumor response. Plus, with a market capitalization (USD) of only $18 million, the upside looks tremendous if the Phase 1/2 trial succeeds.
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