Our lead oncology drug candidate VB-111 (ofranergene obadenovec) is the first VTS™-based agent for cancer therapy.
VB-111 is a unique biologic agent that uses a dual mechanism to target solid tumors:
- Based on a non-integrating, non-replicating, Adeno 5 vector, it utilizes VBL’s proprietary Vascular Targeting System (VTS™) to target the tumor vasculature for cancer therapy. Unlike anti-VEGF or TKIs, VB-111 does not aim to block a specific pro-angiogenic pathway; instead, it uses an angiogenesis-specific sensor (VBL’s PPE-1-3x proprietary promoter) to specifically induce cell death in angiogenic endothelial cells in the tumor milieu. This mechanism retains activity regardless of baseline tumor mutations or the identity of the pro-angiogenic factors secreted by the tumor and shows activity even after failure of prior treatment with other anti-angiogenics.
- Moreover, VB-111 induces specific anti-tumor immune response, which is accompanied by recruitment of CD8 T-cells and apoptosis of tumor cells.
VBL has obtained Fast Track designation for VB-111 in the United States for prolongation of survival in patients with glioblastoma that has recurred following a treatment with standard chemotherapy and radiation; we have also received Orphan Drug designation in both the United States and Europe.
VB-111 successfully demonstrated proof-of-concept and survival benefit in Phase 2 clinical trials in rGBM, thyroid cancer and ovarian cancer.
- Preclinical Insights: Preclinical pharmacological and toxicology studies on VB-111 have shown tissue specificity for the tumor tissue, no significant damage to normal non-cancerous tissues or to the normal blood vessels in the body, and a more than 90 percent reduction in metastatic lung cancer model with one injection, as well as similar efficacy in other tumor models.
- Phase I “all comers” Clinical Trial: We conducted our Phase 1 “all comers” clinical trial of VB-111 in the United States as an open-label, dose-escalating trial to assess the safety, pharmacokinetics and pharmacodynamics of VB-111 in 56 patients with advanced metastatic cancer. The trial was performed at multiple centers and was initiated as a single dose trial. A statistically significant improved overall survival in the VB-111 therapeutic dose cohort as compared to other cohorts was seen. In addition, there was a trend of improvement in the progression free survival rate in response to VB-111 at the therapeutic dose. Following prolonged stability, a partial response, or both, in several patients after treatment with a single dose, we enrolled patients into two additional dose cohorts who received multiple therapeutic doses of VB-111 in two specific tumor types.
A manuscript detailing our Phase 1 study can be found here: http://clincancerres.aacrjournals.org/content/19/14/3996.long
- Phase II Clinical Trials:
VBL’s Phase 2 multi-center study for VB-111 was designed to determine the safety, tolerability and efficacy of VB-111 in patients with rGBM. A total of 46 patients were enrolled in two sequential cohorts. VBL previously reported that the study met the primary endpoint of statistically-significant increase in median overall survival, with 59 weeks in patients treated continuously with VB-111, compared to 32 weeks in patients with only one dose (in median) of VB-111 (p=0.048), both groups having received Avastin upon progression after a short course of VB-111. The 12-Month overall survival was 57% in the VB-111 continuous exposure cohort, compared with only 24% in historical pooled Avastin trials (p=0.03).
At ASCO 2017, VBL presented additional analyses from the Phase 2 study, which demonstrate that tumor growth kinetics was significantly attenuated upon longer treatment with VB-111.
In addition, at the 2016 ASCO meeting, VBL reported results from a Phase 1/2 trial of VB-111 in patients with recurrent platinum resistant ovarian cancer. The data demonstrate a median overall survival of 810 days in the VB-111 therapeutic dose arm, versus 172 days in the low dose arm, a result that was statistically significant. There was also a durable doubling in the response rate, as measured by a reduction in the CA-125 biomarker, compared to historical rates of Avastin® (bevacizumab) plus chemotherapy in ovarian cancer. Durable RECIST responses and disease stabilizations were also observed. An immunotherapeutic effect was also observed in biopsies taken from patients. The trial was conducted at Massachusetts General Hospital and Dana Farber Cancer Institute, Boston, MA. VBL is planning to launch a Phase 3 pivotal study in platinum-resistant Ovarian Cancer in the fourth quarter of 2017.
We also conducted an exploratory Phase 2 clinical trial in the United States as an open-label, dose- escalating trial to assess the safety and efficacy of single or multiple doses of VB-111 in patients with advanced, recently progressive differentiated thyroid cancer that is unresponsive to radioactive iodine. This trial met its primary endpoint, which was defined as 25% progression-free survival at 6 months (PFS-6), in heavily-pretreated patients with late-stage disease. The primary endpoint of the trial, defined as 6-month progression-free-survival (PFS-6) of 25%, was met with a dose response. Forty-seven percent (47%; 8/17) of patients in the therapeutic-dose cohort reached PFS-6, versus 25% (4/12) in the sub-therapeutic cohort, both groups meeting the primary endpoint. Reduction in tumor measurement after the first dose was seen in 44% (7/16) of patients in the therapeutic-dose cohort, compared to 9% (1/11) in the sub-therapeutic-dose cohort. An overall survival benefit was seen with a tail of more than 40% at 3.7 years for the therapeutic-dose cohort (mOS 684 days). This is similar to historical data for pazopanib* (Votrient®), a tyrosine kinase inhibitor; however, most patients in the VB-111 study had tumors that previously had progressed on pazopanib or other kinase inhibitors. VB-111 was well-tolerated in this study, with no signs of clinically significant safety issues.
VBL is planning to launch an exploratory study of VB-111 in combination with a checkpoint inhibitor in the first quarter of 2018.
- Phase III Pivotal clinical trial – VBL Therapeutics’ pivotal Phase 3 GLOBE trial of VB-111 in rGBM is ongoing under a special protocol assessment granted by the FDA.
Detailed information on these clinical trials can be found at www.clinicaltrials.gov
VBL’s pivotal Phase 3 GLOBE study in rGBM, comparing VB-111 in combination with Avastin to Avastin alone, is currently being conducted in the US, Canada and Israel. Enrollment in the study, 256 patients in total, was completed in December 2016, five months ahead of schedule. The study is proceeding under a Special Protocol Assessment (SPA) granted by the U.S. Food and Drug Administration (FDA), with full endorsement by the Canadian Brain Tumor Consortium (CBTC). The company expects top-line results from the full dataset in early 2018.