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 may retain activity regardless of baseline tumor mutations or the identity of the pro-angiogenic factors secreted by the tumor and may show 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.
VB-111 Clinical development overview:
- 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 activity 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 evaluate 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 (mOS), with mOS of 414 days in patients treated continuously with VB-111, compared to 223 days in patients with only one dose (in median) of VB-111, both groups having received Avastin upon progression after a short course of VB-111 (intention to treat population; p=0.043). The 12-Month overall survival was 57% in the VB-111 continuous exposure cohort. In historical pooled Avastin trials, the 12-Month overall survival was only 24% (p=0.03).
At ASCO 2017, VBL presented additional analyses from the Phase 2 study, which demonstrate that tumor growth kinetics were significantly attenuated upon longer treatment with VB-111.
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. VB-111 was also granted Orphan Designation for treatment of malignant glioma by the FDA, and for treatment of glioma in Europe.
VB-111 was also studied in a Phase 1/2 trial of in patients with recurrent platinum resistant ovarian cancer. Data demonstrate a median overall survival of 498 days in the VB-111 therapeutic dose arm, versus 172 days in the low dose arm, a result that was statistically significant (p=0.03). There was also a durable response rate, as measured by a reduction in the CA-125 biomarker. 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.
VB-111 has received an Orphan Designation for the treatment of ovarian cancer by the European Medicines Agency (EMA).
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 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 with 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). Historical data for pazopanib* (Votrient®), a tyrosine kinase inhibitor demonstrated similar results; 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 trials:
rGBM – VBL’s pivotal Phase 3 GLOBE study in rGBM, comparing VB-111 in combination with Avastin to Avastin alone, was conducted in the US, Canada and Israel, and enrolled 256 patients in total. GLOBE was conducted 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). In March 2018, we announced top-line results from the GLOBE study, which showed that the study did not meet its pre-specified primary endpoint of overall survival (OS) or the secondary endpoint of progression-free survival (PFS). We are still performing analyses on the data from GLOBE study, which we intend to report later this year. However, Investigating the Phase 3 data in comparison to the Phase 1 and Phase 2, so far did not reveal any difference in the prognostic factors which may explain their different outcomes.
To the best of our knowledge, the only difference was in the Phase 3 trial regimen, as dictated by the Special Protocol Assessment (`SPA`) for the GLOBE study. In the Phase 2 study of VB-111 in rGBM, which demonstrated meaningful OS benefit, VB-111 was given alone until progression (`priming`). On the other hand, in the Phase 3 trial there was no priming with VB-111, which was administered in combination with Avastin from the beginning. We believe that there is a good possibility that this regimen may have impaired the efficacy of VB-111 and thus resulted in an unsuccessful readout.
As a result of the failure of the GLOBE trial to meet its pre-determined endpoints, we have decided to put further development of VB-111 in rGBM on hold at this point. However, we still believe in the biological activity of VB-111 as seen in our Phase 1 and Phase 2 trials, and do not think that results of the particular GLOBE study that investigated VB-111 in combination with bevacizumab in rGBM, will necessarily have implications on the prospects for VB-111 in other tumor types, in different patients populations, or in different regimens.
VBL Therapeutics’ pivotal Phase 3 OVAL trial of VB-111 in recurrent platinum-resistant ovarian cancer was launched in December 2017
Our OVAL phase 3 potential registration study of VB-111 in platinum resistant ovarian cancer is conducted in collaboration with the GOG Foundation, Inc., a leading organization for research excellence in the field of gynecologic malignancies. OVAL has been designed to enroll up to 350 adult patients at approximately 70 clinical sites in the United States and Israel.
We are in the process of amending the protocol to include an interim analysis for evidence of an early efficacy signal with a potential readout from this analysis in the fourth quarter of 2019.
VB-111 has received an orphan designation for the treatment of ovarian cancer by the European Medicines Agency.