VBL’s lead compound VB-111 is the first highly targeted anti-angiogenic agent for the specific inhibition of tumor vascular growth to use VTS™, for cancer therapy. VB-111 is an IV-administered anti-angiogenic agent for the treatment of solid tumor indications, with current clinical trials in rGBM, thyroid cancer and ovarian cancer.
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.
VBL designed VB-111 to address oncology indications, specifically solid tumors, by selectively targeting the blood vessels required for tumor growth and inducing the programmed cell-death process, or apoptosis, of cells in those blood vessels. In addition, an immunotherapeutic effect was also observed in biopsies taken from patients. H&E and immunohistochemistry staining showed regions of apoptotic cancer cells and infiltration of cytotoxic CD8 T-cells following treatment with VB-111. VB-111’s mechanism of action is independent of tumor-specific mutations, which we believe makes it less susceptible to resistance and, therefore, potentially applicable for a broader patient population than current therapies.
- 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 I/II and Phase II Clinical Trials: Our multi-center Phase 2 study of VB-111 in patients with recurrent glioblastoma (rGBM) met its primary endpoint and showed statistically significant overall survival benefit in patients treated with VB-111 continued with VB-111 in combination with Avastin™ upon disease progression (Treatment Through Progression cohort), compared to patients treated with VB-111 followed by Avastin™ alone, upon disease progression (limited exposure cohort).
On June 2016, at the 2016 American Society of Clinical Oncology (ASCO) annual meeting, VBL reported new data comparing Phase 2 clinical outcomes with VB-111 with pooled data from 8 studies that investigated Avastin in recurrent glioblastoma (rGBM). In the Phase 2 VB-111 trial, the median overall survival of patients who received continuous exposure of VB-111 in combination with Avastin was 59 weeks. This is compared to 32 weeks in the pooled data from the 8 studies in the meta-analysis (p= 0.0295 Hazard Ratio 0.62, 95% CI: 0.40-0.96). Median survival ranged from 26.0 weeks to 45.7 weeks in the meta-analysis. Overall survival at 12 months for patients on continuous exposure of VB-111 was 57%, compared to 24% overall survival (range 16% – 38%) for the pooled data (p= 0.03).
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 is conducted at Massachusetts General Hospital and Dana Farber Cancer Institute, Boston, MA.
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.
- 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