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I like the 3 milestones for 2017 and the confirmation that the company is funded until 2019.
VBLT will soon have 2 phase 3 candidates, with the rGBM announcing its interim results right around / before ovarian starts its phase 3.
2017 is going to be an interesting year. Hope it's going to be a great one!
So 2 scenarios would trigger interim:
1) 105 deaths occur first then 128 patients have more than 12 months potential follow up.
2) 128 patients have more than 12 months potential follow up then 105 deaths occur.
If I'm reading it right ...
Scenario 1 would happen first because it's time-based.
Scenario 2 would be due to drug effectiveness and could (hopefully) take longer to trigger.
davidal66 ... I think you're reading it right.
256 total
50% = 128 so ... 105 deaths can occur but 128 patients may not have more than 12 months potential follow up. Likewise, 128 patients have more than 12 months potential follow up but 105 deaths have not occurred. Both have to happen to trigger interim. That is interesting.
Thanks for that analysis! Hope you stay and contribute.
Real news is FDA approval of when interim and final analyses will be triggered - but it is good to get confirmation that enrollment is complete (which is fast!)
From news release:
VBL has also received FDA approval for adjustments in the GLOBE protocol. These major modifications relate to the triggers for the interim and final analyses. The SPA covering GLOBE remains in place. Originally, the interim analysis in GLOBE was to be conducted after 91 deaths. The modified protocol specifies that it will be conducted after 105 deaths, and after 50% of the patients have more than 12 months potential follow up, whichever occurs later. The final analysis will be conducted at 189 deaths (75% of events), versus the original planned for 151 deaths (60% of events).
============
Since first patient dosed was in August 2015, it took approximately 17 months for full enrollment. Midway point of enrollment timing wise was around May 2016 ... so 12 month survival for approximately 50% of the population (assuming it corresponds with timing) is around May 2017.
Expecting midyear news ... the later the better.
That is possible. Whatever they're using the funds for, they're going to have to disclose it on the next call. Imagine the CEO saying something like you describe ... fireworks would go off (in a good way) but then people would also question how he knows about the data.
Regarding NASH, the CEO indicated that they want a partner and don't want to pursue it alone ... because they are an oncology company .. but this comment in the prior Q1, and the lack of a partnership announcement all year, makes me wonder if 1) they didn't find a win-win type partnership and because of this 2) they will use the funding to move these NASH candidates forward.
==========
we're working on the second stage of the disease when it move to inflammation, because 201 is a Phase-2-ready drug, we believe that the data that we show in the preclinical is as good as many of the compounds that went into a Phase 2 and there would be someone that will want to develop it, but they want to make it very clear that we are focused on oncology, we have lot on the plate and we are not going to do this trial by ourselves
==========
davidal66 ... I would agree that the additional funding will be directed most likely towards something that has not been discussed in detail -- but I would assume the details will come in the next call.
All speculation here but it could be any of these things:
New HQ building. The company has been on record in saying that the new HQ building will not impact their cash position. So this should not be an issue. Would be a complete shocker if this was the reason.
VB-111: I believe the company has said they have enough money to fund ph3 rGBM. Perhaps the money is in anticipation for the funding needed after ph3? But the end of ph3 won't happen until 2018. Why do the funding in 2016? And why not do the funding when the stock price is higher (assuming news of approval comes out). So this scenario doesn't make sense.
VB601, NASH and other pre-clinical candidates: None of these on their own requires $20MM for ph 1/2, imo. Perhaps it is to fund multiple candidates? In Q2 2015 the company was burning $2.5MM per quarter. This was when VB-111 was in ph2 for rGBM and earlier phases for Ovarian and Thyroid. But keep in mind the burn rate was to also fund general and administrative costs. The trial costs had lower burn rates on their own. So this $20MM funding is pretty significant even if it's for the pre-clinical candidates.
Acquisition? Highly unlikely but who knows?
The last funding is definitely a head scratcher. Hopefully 2017 is a great year and we are all pleasantly surprised by the reason.
2017 - looking ahead
Every time I think about what's upcoming, I reflect back to the 1 slide that I saw presented at SNO regarding the company's VTS platform:
Anti angiogenesis
Pipeline Product / Promoter / Transgene / Gene Therapy Mechanism / Development stage
VB-111 / PPE-1-3X / Fas-c / Cell death induced by the Tumor itself / Phase 3
VB-311 / PPE-1-3X / TK / Inducible system. Cell death only upon supply of oral drug / Pre-clinical
VB-511 / PPE-1-3X / E1 / Conditional replication-efficient virus / Pre-clinical
Pro angiogenesis (Ischemia)
Pipeline Product / Promoter / Transgene / Gene Therapy Mechanism / Development stage
VB-211 / PPE-1-3X / VEGF/PDGF / Targeted delivery of growth factors / Pre-clinical
VB-411 / PPE-1-3X / Stabilized HIF1?/ Targeted expression of pro-angiogenic master regulator / Pre-clinical
In addition to the NASH candidates like VB-201 and VB-703.
Aside from VB-111, everything else is a long ways off but there are some very interesting developments ... especially VB-311 and the NASH candidates, imo. 2017 is a make-or-break year for the company. 2017 is when VB-111 will mature with data, which we all have been patiently waiting to see.
Still, I will be interested in the other pipeline products and see if they move ahead in their development. I am also interested in learning why the company needed the additional funding - how are they all are related? 2017 will be an interesting year!
Speaking of filling up fast, Stanford is no longer accepting patients.
https://med.stanford.edu/clinicaltrials/trials/NCT02511405
100% agree with your assessment davidal66. Phase 3 failures can be traced to a number of things, including what you've stated and things like changing the criteria from phase 2 to phase 3.
But my response was to oren1976 who asked, "How can u believe him when he says he is blinded while a minute after he says the death rate is not high he is not suppose to know death rate if blinded no ?"
So I just provided another example of where a researcher discloses information from a supposedly blinded study. When the information came out, her statement proved correct.
Enjoy reading your insights!
Not a direct answer to your question, but a similar thing happened with DCVax:
============
Discussing the DCVax-L phase III study, Liau said all enrolled brain tumor patients were living longer, which she described as a "good thing." But then Liau noted that patients living longer "was not really helping our study" because it hurts the chance of showing a difference in survival between the DCVax-L and placebo arms of the study. Without that difference, the study fails.
Liau, perhaps realizing she spoke too openly about the DCVax-L study, goes on to say that she doesn't have any data from the study because it's still ongoing and blinded.
============
So it has happened before. In VB-111's case the data provided was good so I'll take that as we head into 2017.
Article:
https://www.thestreet.com/story/13452761/1/northwest-bio-blames-short-sellers-not-warning-from-expert-doctor-for-stock-plunge.html
No, you're right about total recruitment; they're still recruiting but close to completion. I was talking about the number of patients needed to get the X number of events that would trigger the interim.
I think a good chunk of the 252 were in the trial after 1 year so we should have data coming from the trial mid-2017 or late-2017 at the latest, imo.
"Median overall survival for patients on continuous exposure of VB-111 was 59 weeks, compared with 32 weeks in historical pooled Avastin trials (p= 0.0295)."
Some factors to consider:
1) 32 weeks = 8 months, 59 weeks = 14 months
2) Let's say it take 1 yr to complete recruiting (this is a conservative estimate since the company is 5 months ahead of schedule) then recruiting was completed by August 2016. We should know the median OS at the very latest by the end of 2017
2017 is the make or break year for this company.
I believe the answer was in response to a question asking if the results will be publicly announced and the criteria for early termination. The CEO then responded that the data will be blinded even at the interim, and that he doubts early termination would happen at or before the interim ... something like that.
But he's blinded to the data, so he's only providing an educated guess.
Interesting tidbit on the DSMC:
A DSMC may occasionally recommend to the sponsor that a study be stopped before the planned enrollment is complete, either because of a safety problem or because patients are doing so well on the new treatment that it would be unethical not to provide all patients with the study drug as soon as possible. http://www.medscape.com/viewarticle/409917_2
I wonder where they draw the line? Multiple trials have shown Avastin 12-month survival to be around 28%. If VB-111 overall survival is 50% or higher after 12 months (and 70% of the Avastin only side have passed away - unfortunately) then would it be unethical if the trial is not stopped?
Another data point to confirm VB-111's safety, which has been mentioned in the rGBM, Ovarian and Thyroid trials. The adverse effects in other rGBM drugs can be serious but patients have little choice but to take them. Even Avastin has serious (fatal) GI side effect.
Gilead recently announced this on the conference call: "As you may know there were two recent setbacks with JAK1 inhibitors, one of them was a discontinuation of a Phase 3 program because of CNS toxicity and the other one was withdrawal of an NDA because of cardiovascular adverse events."
So getting DSMC approval is huge.
More information on the DSMC:
The Data and Safety Monitoring Plan (DSMP) was developed referencing Food and Drug Administration (FDA), National Institutes of Health (NIH), and National Cancer Institute (NCI) guidelines.
The Data and Safety Monitoring Committee (DSMC) oversees internal monitoring functions by reviewing study conduct for consistency with Good Clinical Practice (GCP), compliance with federal regulations, and production of high quality scientific data. The DSMC is comprised of physician investigators, internal monitors, and administrative staff. The DSMC monitored studies are reviewed based on their assigned risk level and, at minimum, will receive annual reviews. The DSMC monitors will routinely assess study conduct, reviewing all study aspects according to the monitoring plan. Such reviews include informed consent documentation, eligibility criteria, protocol compliance, and source document verification for data accuracy. Additionally, query resolution (clarification or correction of inaccurate data), occurrence and reporting of adverse events, test article accountability, and maintenance of essential documentation will be reviewed.
https://winshipcancer.emory.edu/research/clinical-trials-office/data-and-safety-monitoring-committee.html
I think the company's onto something; it's just a matter of time.
I would guess 2-3 years.
VB-703 seems to be the NASH jewel for VBLT.
http://link.springer.com/article/10.1007/s10620-016-4159-5
In the current report, we investigated the effect of VB-201 treatment on the development of NASH and liver fibrosis in a mouse model. In addition, we used VB-703, an unreported lecinoxoid designed in silico for improved efficacy, that does not affect monocytes migration, but exhibits increased inhibition of TLR-4 over VB-201. The results demonstrate that lecinoxoids restrict liver inflammation and profoundly ameliorate liver fibrosis.
The results demonstrate that VB-703 inhibits TLR-4-mediated signaling events and cytokine production with a profoundly higher degree of activity than VB-201 (Fig. 2a, b) but similar to VB-201’s inhibitory effect on TLR-2-mediated phosphorylation (Fig. 2c). Moreover, VB-703 showed annulled activity in the case of monocyte migration (Fig. 2d).
Analysis of inflammation mediators IL-1ß, IL-6, MCP-1, and IL-12/23p40 in the liver of NASH-induced mice showed that VB-703 for the most part significantly inhibited expression of pro-inflammatory mediators, whereas VB-201 significantly attenuated only the expression of IL-12/23p40 (Figs. 3a–d).
The results, presented in Fig. 4a, b, demonstrate that VB-703, more than VB-201 and even telmisartan, significantly restricted the development of liver fibrosis.
Functionally, VB-201 differs from VB-703 in its ability to also inhibit monocytes migration, but it is a weaker antagonist of TLR-4 than is VB-703. Nevertheless, our results demonstrate that significant effects of lecinoxoids on liver inflammation could be attained by targeting TLR-2 and predominantly TLR-4, since VB-703 was superior to VB-201 in inhibiting all of the inflammation mediators tested.
To conclude, small molecules oxidized phospholipids that strongly antagonize TLR-4 and inhibit monocytes migration should be further explored for their potential to treat subjects with NASH and liver fibrosis.
Check out this Tumor Stage Classification study involving VB-111.
https://www.sigport.org/documents/pca-based-algorithm-longitudinal-brain-tumor-stage-classification-dynamical-modeling-tumor
These quotes are confirming:
“They have 20 agents that they can excrete to stimulate the buildup of new blood vessels. For this reason, trying to block one or two of these factors will not be potent enough. We took another approach — when the tumor tries to build these new vessels, we activate a deadly gene, targeting only the angiogenic blood vessels.”
“We are actually also exposing the tumor to the immune system — because the immune system recognizes the tumor with the virus and sets out to fight both the virus and the tumor. With our drug, we are killing the blood vessels, but we are also bringing the immune system to the tumor itself.”
Thanks for the article. Really confirms all the things we've been discussing.
Additional funding is interesting. On the Q3 call they said, "We continue to reiterate our guidance that our resources would be sufficient to meet the working capital requirements fund planned operation and supported best advancement of platform technologies into 2019."
Is this a signal for a new development?
Regarding Adam F, I cannot believe how many people foolishly follow him. He acts like a child and resorts to name calling. He's a big FUDster.
I was in ARIA when he said it was a crap company with no viable product. That was when ARIA was in the 5's. I ignored his FUD because I knew about the company's pipeline.
Same story here. Adam F is spreading is FUD again. Except this time, I actually think VBLT has more potential -- much more potential -- than ARIA.
Of course, time will tell. For these types to companies, you have to do your research and make a decision based on that. Ignore the noise.
In the last call, I think one questioner asked him to confirm the numbers that he provided in the prior call - 91 events for interim and 151 for full. That's when he spilled the beans and said he is meeting with the FDA to make some changes.
So I think it was more asking a good question than knowing something ahead of time. But I agree with you. In general, it seems like these investors know a little bit more than the rest of us and as we have seen in the past, not everything they do is legal.
Regarding the drop out rate. The CEO did say that the drop out rate is "very low" on the last conference call.
On the recruiting success, he also said that he is guessing and his guess is that there is high demand for VB-111 due to its success in the prior phase.
The company is blinded to the data so only the investigators know what is really going on ... and they're not talking.
Definitely looking forward to the update on the outcomes from the discussions with the FDA.
You could be right. My perspective: When I hear that enrollment is ahead of schedule, I take that as total enrollment - both control and combo arms. Doesn't make sense for them to say that enrollment is ahead of schedule but there are issues with the control arm.
The metrics for Avastin are well supported by thousands of patients. They are well documented. I'd be surprised if VB-111's control arm with Avastin only shows anything different than the past results.
Thanks for your perspective. The upcoming announcement will shed light on all of this.
One thing to note is that trial recruiting is done by word-of-mouth in the medical industry - there are FDA restrictions on what a company can do to inform the industry and patients on the trial.
My read into being 5 months ahead of schedule is that
1) The medical community is cautiously optimistic about VB-111. They like what they are seeing so far. Doctors are recommending VB-111 to their rGBM patients; and
2) With the internet and support groups, patients are now more informed. They know about prior trials and they are getting recommendations from other patients, who have had good success with VB-111.
Phase 3 recruiting timeline was based on phases 1 and 2 rates, multiplied by the number of recruiting sites involved. To be 5 months ahead means that there was a huge spike in interest from both the medical and patient communities.
My thoughts on the increase in # of events:
1) Recruiting / trial is 5 months ahead of schedule: This allows for the additional events to be added without affecting the timeline.
2) More likely of an early FDA approval when there are more events reported. Instead of reporting interim early (because of the 5 month lead), wait a few months to get more events. The goal is to get FDA approval so why not try to get early approval by reporting more events. My guess is that this is the negotiation going on with the FDA.
Yes, and as we have discussed, the correlation with the feverish response is very interesting. Feverish responses also happened in patients that have successful CAR-T therapies ... and as we have seen recently, CAR-T can be effective but it certainly is not safe.
Most important: Confirmation VB-111 is safe in 3 indications. With all trials and phases combined, this shows that VB-111 is safe in over 300 patients. It also shows that VB-111 is so far very effective in thyroid, ovarian and brain cancers.
Safety is a huge issue in these types of drugs, and VB-111 has shown to not only be safe but also safe when combined with other therapies.
Statistical significance means that the sample size is too low - does not matter if the trial outcome is positive or negative. For the trial, they prefer positive results over negative but it is meaningless due to the low sample size.
It is independent of other trials.
Thyroid met its endpoint but the company will not put resources on it. They are only putting resources into rGBM and ovarian.
I thought it was a very good update. I made note of the following:
1) GLOBE recruitment is 5 months ahead of schedule. This accelerates the trial, including the interim analysis. Recruiting is almost complete.
2) Interim analysis is now scheduled for mid-2017, but it could be later (if VB-111 outperforms expectations).
3) He seems to be hinting at a low death rate and a potential for the FDA to terminate the trial early if they observe that the OS rate is better than historic data. Avastin has no OS benefit .. or PFS benefit. So VB-111 only has to improve on the median OS, which I believe is in the 3 to 3.5 month range.
4) They are meeting with the FDA to agree on the number of events. This is something to look for in next quarter's meeting.
5) The company is only going to run two trials: GLOBE and ovarian (phase 3 coming after FDA approval)
6) They have an agreement with the Israeli government for facilities. That's why the new facilities do not have a huge impact on their cash position.
7) Sounds like there are companies that are interested in working with (or acquiring?) VBL but the CEO thinks the valuation is too low.
Amgen's Imlygic is virus-based, so Amgen does have some interest/expertise in this area.
Regarding the fever marker ... the CEO first brought it up as something they'll look into in ph3. Then, the patients started to notice it. Now, the medical community is picking up on it. I think there is something there.
I agree with your thoughts: either a significant partnership or a buy out. Did you catch that this research was "funded by Eisai, Merck, Genentech, Amgen, BioMimetix Pharmaceutical, Inc., VBL Therapeutics and Agios"?
Some major players funding the research.
Yes, that's why I brought that part to the top. It also spiked my interest as well. I think many in the medical community is starting to pay attention to VB-111 and hoping that it makes it through phase 3.
They are already speculating what it can do in combination with other therapies.
This is a MUST read.
Amazing article about the future of VB-111.
VB-111 represents one such modality that is being actively investigated in high-grade gliomas. As evidenced above, VB-111 can be combined safely with other antiangiogenic therapies. It is intriguing to consider the combination of VB-111 with standard cytotoxic agents, or even with the combination of immunotherapy. In the rapidly evolving field of oncology, the latter combination may prove to be the more likely scenario that may be examined in future clinical trials. Thus, the onus will be to demonstrate that unleashing a host immune response against highly vascular malignancies can be safely done in the setting of TNFa-mediated endothelial cell apoptosis; a consideration especially important in the setting of those patients who develop fevers while receiving VB-111 compared to those that do not. With respect to the latter group of patient, a possible hypothesis to consider is whether immunotherapy may improve response rates in this population.
Overall, VB-111 represents an important step forward to using genetically engineered biotherapy for the treatment of high-grade gliomas. Its safety, efficacy, and comparative benefit warrant further exploration in large clinical trials.
FULL article: http://www.tandfonline.com/doi/full/10.1080/21678707.2016.1235971
Abstract
Introduction: High grade gliomas continue to represent a group of cancers that are difficult to control with current cytotoxics and antiangiogenics. With tumor angiogenesis representing a critical mechanism, there is an unmet need for novel types of treatment that can hone in on this important pathway of tumorigenesis.
Areas covered: Virotherapy is a promising modality of cancer treatment that is defined by genetic manipulation of a virus to preferentially target neoplastic cells. VB-111 (ofranergene obadenovec) is a genetically modified adenovirus that is designed to selectively target tumor-associated endothelial cells. Utilizing PubMed and MEDLINE® databases, we identified key preclinical and clinical data pertaining to VB-111. We then reviewed ClinicalTrials.gov to determine the status of ongoing research.
Expert opinion: Demonstrating safety and showing signs of efficacy in early phase clinical trials, VB-111 is being studied in combination with and without bevacizumab in a large phase 3 trial for recurrent glioblastoma. Given the data, VB-111 is a unique viral-mediated, antiangiogenic approach that has significant potential to make an impact in the field of oncology and neuro-oncology. We agree with the continued study of this agent in expanded and randomized cohorts to determine if VB-111 can indeed impact survival in glioblastoma.
KEYWORDS: VB-111, virotherapy, angiogenesis, adenovirus, glioblastoma, glioma
1. Introduction
The treatment of gliomas has been a vexing discipline in the field of oncology. With a broad array of subtypes and pathogenic mechanisms that are not yet fully understood, currently approved regimens for the management of gliomas have had limited success. Gliomas are subdivided into histologic categories based on glial tissues of origin, as well as microscopic features connoting low- and high-grade characteristics. With respect to the topic at hand and for the purposes of this review, we will focus on high-grade gliomas given the urgent need for improved modalities of treatment.
High-grade gliomas are histologically defined by a propensity for neovascularization, degrees of anaplasia, areas of necrosis, and a relatively high growth index compared to their lower grade counterparts. Although various glial cell types can exhibit these features, the most common and most malignant of these are glioblastoma (GBM). With an annual incidence of less then 2% of all diagnosed malignancies, GBM still represents a disproportionately high rate of disease-specific morbidity relative to more common malignancies (i.e. breast, colon, and lung) [1 Ostrom QT, Gittleman H, Fulop J, et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2008–2012. Neuro Oncol. 2015 Oct;17(Suppl 4):iv1–iv62.
[CrossRef], [PubMed], [Web of Science ®]
The current standard of care (SOC) was introduced by Stupp et al. in 2005 as a combination regimen that included surgery, radiotherapy, and concurrent temozolomide, followed by six cycles of adjuvant single-agent monthly temozolomide. This approach yielded a superior 1- and 5-year median overall survival (OS) advantage compared to radiation and subsequent chemotherapy (27% vs. 11% and 10% vs. 0%; hazard ratio [HR] 0.63, 95% CI 0.53–0.75, respectively) [2 Stupp R, Mason WP, van den Bent MJ, et al. European Organisation for research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. N Engl J Med. 2005 Mar 10;352(10):987–996.
[CrossRef], [PubMed], [Web of Science ®]
]. It has been the SOC for newly diagnosed patients for over a decade.
In the setting of recurrent disease, there are few options. Given that high-grade gliomas are highly vascularized tumors, bevacizumab (BEV) represents the backbone of most second-line therapy for recurrent disease. BEV is a humanized IgG1 monoclonal antibody that targets vascular endothelial growth factor (VEGF) and prevents its interaction with the VEGF receptor on the malignant cell surface [3 Glade-Bender J, Kandel JJ, Yamashiro DJ. VEGF blocking therapy in the treatment of cancer. Expert Opin Biol Ther. 2003 Apr;3(2):263–276.
[Taylor & Francis Online], [Web of Science ®]
]. Thereby, it is postulated that BEV normalizes tumor vascular supply and may improve cytotoxic chemotherapeutic delivery, with the added potential benefit of decreasing the propensity of tumors to form new vasculature [3 Glade-Bender J, Kandel JJ, Yamashiro DJ. VEGF blocking therapy in the treatment of cancer. Expert Opin Biol Ther. 2003 Apr;3(2):263–276.
[Taylor & Francis Online], [Web of Science ®]
]. The initial approval of BEV was based on its clinical response rate in patients with recurrent GBM, as well as its impact on quality of life and patient reliance on glucocorticoids for symptom control [4 Kreisl TN, Kim L, Moore K, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009;27(5):740.
[CrossRef], [PubMed], [Web of Science ®]
]. Friedman et al. went on to demonstrate that antiangiogenic therapy can be safely combined with conventional cytotoxic chemotherapy in the setting of recurrent GBM. Although the combination arm had slightly more toxicity compared to patients who received BEV alone, the group receiving BEV and irinotecan demonstrated a trend toward improved progression-free survival (PFS); however, there was no OS difference between the two groups [5 Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009 Oct 1;27(28):4733–4740.
[CrossRef], [PubMed], [Web of Science ®]
].
Synergizing BEV in combination with cytotoxic therapy has been studied but has yet to be optimized in the setting of high-grade glioma. Late phase clinical trial data from EORTC 26101 compared the addition of BEV to lomustine versus lomustine alone in 437 patients who had a first recurrence of disease after SOC therapy. With approximately two-thirds of patients in the combination arm, the investigators concluded that OS was not superior to lomustine alone (HR 0.95, CI 0.74–1.21, p = 0.65) [6 Wick A, Brandes AA, Gorlia T, et al. Phase III trial exploring the combination of bevacizumab and lomustine in patients with first recurrence of glioblastoma: the EORTC 26101 trial. Neuro Oncol. 2015;17(suppl 5):v1.
[CrossRef], [PubMed], [Web of Science ®]
]. In addition to BEV, small-molecule inhibitors of the VEGF pathway have also been investigated; however, none has shown significant improvement in OS to warrant approval within recurrent GBM [7 Batchelor TT, Mulholland P, Neyns B, et al. Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. J Clin Oncol. 2013;31(26):3212.
[CrossRef], [PubMed], [Web of Science ®]
With its wide spread adoption in multiple cancer types, angiogenesis inhibition via VEGF blockage (both monoclonals and small molecules) has yielded clinically significant complications in a subset of patients, such as hypertension, proteinuria, thromboembolic events, and cardio- and cerebro-vascular events [8 Economopoulou P, Kotsakis A, Kapiris I, et al. Cancer therapy and cardiovascular risk: focus on bevacizumab. Cancer Manag Res. 2015 Jun;3(7):133–143.
[CrossRef]
]. There is also mounting evidence that anti-VEGF therapy with BEV may contribute to a more invasive phenotype in recurrent GBM [9 de Groot JF, Fuller G, Kumar AJ, et al. Tumor invasion after treatment of glioblastoma with bevacizumab: radiographic and pathologic correlation in humans and mice. Neuro Oncol. 2010 Jan;12(3):233–242.
[CrossRef], [PubMed], [Web of Science ®]
,10 Delay M, Jahangiri A, Carbonell WS, et al. Microarray analysis verifies two distinct phenotypes of glioblastomas resistant to antiangiogenic therapy. Clin Cancer Res. 2012 May 15;18(10):2930–2942.
[CrossRef], [PubMed], [Web of Science ®]
].
As evidenced above, there is an urgent need to improve upon the treatment of GBM. Virotherapy is one such modality that is being explored as a novel means of treatment. The impact of viral infections on cancer has been anecdotally observed as far back as the 1890s; however, its practical application has been limited in scope and practice until recently [11 Dock G. The influence of complicating disease upon leukemia. Am J Med Sci. 1904;127:563–592.
[CrossRef]
]. In general, the application of viruses to the treatment of cancer relies on either a direct oncolytic effect or an indirect means of stimulating the immune system against a malignancy by way of genetically modifying viruses to selectively target neoplastic cells. An example of this is talimogene laherparepvec (T-VEC), which was recently approved in the setting of advanced melanoma. T-VEC is a genetically modified herpes simplex virus 1 with attenuated virulence for non-tumor cells and an enhanced replicative capacity in tumor cells [12 Liu BL, Robinson M, Han ZQ, et al. ICP34.5 deleted herpes simplex virus with enhanced, immune stimulating, and anti-tumour properties. Gene Ther. 2003 Feb;10(4):292–303.
[CrossRef], [PubMed], [Web of Science ®]
]. T-VEC is injected intralesionally. Infection leads to viral replication within the cell and subsequent oncolysis. Additionally, the consequent expression of virally encoded stimulates an innate immune response against granulocyte-macrophage colony-stimulating factor (GM-CSF) the infected cell [12 Liu BL, Robinson M, Han ZQ, et al. ICP34.5 deleted herpes simplex virus with enhanced, immune stimulating, and anti-tumour properties. Gene Ther. 2003 Feb;10(4):292–303.
[CrossRef], [PubMed], [Web of Science ®]
,13 Andtback RH, Kaufman HL, Collichio F, et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015 Sep 1;33(25):2780–2788.
[CrossRef], [PubMed], [Web of Science ®]
]. With median OS trending toward significance in a randomized phase 3 trial, intralesional T-VEC was approved by the FDA for the treatment of advanced melanoma after meeting its primary end point of a superior durable response rate compared to subcutaneous GM-CSF alone [13 Andtback RH, Kaufman HL, Collichio F, et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015 Sep 1;33(25):2780–2788.
[CrossRef], [PubMed], [Web of Science ®]
,14 U.S. Food and Drug Administration. 2015. [updated Oct 27; cited 2016 Jan 23]. Available from:
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm469571.htm
2. VB-111: mechanism of action
Ofranergene obadenovec (VB-111) (Box 1) is genetically modified adenoviral construct that is being developed by VBL Therapeutics. Unlike the recently approved T-VEC, the unique anticancer properties of VB-111 stem from its propensity to target tumor vasculature without the need for viral replication and direct oncolysis. The backbone of VB-111 is a nonreplicating adenovirus type 5 (Ad-5) vector. What it lacks in typical virulence, it compensates with its ability to carry a proapoptotic human Fas-chimera transgene under the control of a modified murine pre-pro-endothelin 1 (PPE-1) promoter [15 Varda-Bloom N, Shaish A, Gonen A, et al. Tissue-specific gene therapy directed to tumor angiogenesis. Gene Ther. 2001 Jun;8(11):819–827.
[CrossRef], [PubMed], [Web of Science ®]
]. The integration of modified PPE-1 (termed PPE-1-3x) within the genome of infected angiogenic endothelial cells allows it to be preferentially expressed due to a unique regulatory element. Preclinical models demonstrated that normal blood vessels do not express this promotor sequence [16 Greenberger S, Shaish A, Varda-Bloom N, et al. Transcription-controlled gene therapy against tumor angiogenesis. J Clin Invest. 2004 Apr 1;113(7):10717–11024.
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Box 1. Drug summary
CSVDisplay Table
As the promotor region is transcribed, the Fas-chimera transgene is thus expressed. The product is then incorporated as a transmembrane protein, with its extracellular domain possessing human tumor necrosis factor receptor 1 (TNFR1). Subsequently, the TNFR1 receptor interacts with tumor necrosis factor alpha (TNFa) leading to caspase-mediated apoptosis of angiogenic tumor endothelial cells (Figure 1) [17 Boldin MP, Mett IL, Varfolomeev EE, et al. Self-association of the “death domains” of the p55 tumor necrosis factor (TNF) receptor and Fas/APO1 prompts signaling for TNF and Fas/APO1 effects. J Bio Chem. 1995 Jan 6;270(1):387–391.
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Figure 1. Adenovirus type 5 interacting with cancer-related endothelial cell (1), with subsequent transcription of the Fas-chimera transgene (2), followed by the incorporation of the protein product at the cell surface (3). TNFR1 interacting with TNFa, leading to apoptosis of endothelial cells (4).TNFR1: tumor necrosis factor receptor 1; TNFa: tumor necrosis factor alpha. Source: VBL therapeutic public presentation. Obtained with permission from the company.
3. Preclinical data
Preclinical models assessing the efficacy of VB-111 in high-grade gliomas have demonstrated robust radiographic responses and an OS benefit. Gruslova et al. employed nude rat and mouse xenograft models with intracranially implanted U87MG or U251. Both cell lines were tagged with luciferase, allowing the investigators to use bioluminescence imaging to assess response. After tumors were established, the animals were injected with VB-111 or a control. Survival was in favor of those animals that were injected with VB-111 (log rank p < 0.05). This corresponded to a decrease in tumor volume over time. The antiangiogenic effect of VB-111 was also measured using CD31, a marker for neovascularization. CD31 levels were fivefold higher in the control group compared to the group that received VB-111 (p = 0.022). Additionally, magnetic resonance imaging demonstrated a difference in tumor enhancement between the two groups, with the control group exhibiting a greater relative degree of contrast enhancement throughout the bulk tumor compared to the VB-111 group, which had a propensity to enhance peripherally with centrally necrotic features [18 Gruslova A, Cavazos DA, Miller JR, et al. VB-111: a novel anti-vascular therapeutic for glioblastoma multiforme. J Neurooncol. 2015 Sep;124(3):365–372.
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4. Pharmacodynamics, pharmacokinetics, and metabolism
Data from an early phase clinical trial have provided important insights into the biological behavior of VB-111. In a study by Brenner et al., 33 patients were divided into 7 dosing cohorts, with the viral particle (VP) dose ranging from 1 × 10e10 (cohort 1) to 1 × 10e13 (cohort 7) [19 Brenner AJ, Cohen YC, Breitbart E, et al. Phase I dose-escalation study of VB-111, an antiangiogenic virotherapy, in patients with advanced solid tumors. Clin Cancer Res. 2013 Jul 15; 19(14):3996–4007.
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]. The purpose of the study was to assess various biochemical parameters, safety, and early signals of survival (clinical data discussed below). With respect to biochemical measurements (i.e. pharmacodynamics, pharmacokinetics, and metabolism), serum and urine levels of Ad-5 DNA and Fas-chimera transgene expression were analyzed prior to and after the intravenous administration of each dose using quantitative real-time PCR and reverse transcriptase plus PCR, respectively. All samples were negative for Ad-5 DNA expression prior to administration. After infusion, blood levels of Ad-5 DNA demonstrated a dose-dependent response, and subsequently dropped off by day 56 in all patients. Urine levels of Ad-5 DNA were transiently detectable only within the initial 24 h after infusion. Transgene expression in the blood was negative in all samples after each infusion, suggesting that normal vasculature was not being targeted. A single patient’s subcutaneous metastatic site from esophageal cancer was sampled on days 4 and 28 and revealed detectable levels of Fas-chimera transgene expression, suggesting infiltration by the virus of host tumor vasculature.
5. Clinical data
To date, there have been at least two published patient studies assessing the safety and tolerability of VB-111 in cancer. Although not powered for efficacy, these studies demonstrated encouraging signals of survival benefit that are being explored in expanded patient cohorts and at increasing numbers of institutions. As briefly touched on above, VB-111 was administered intravenously in patients with advanced solid tumors in an open-label phase 1, dose escalation study [19 Brenner AJ, Cohen YC, Breitbart E, et al. Phase I dose-escalation study of VB-111, an antiangiogenic virotherapy, in patients with advanced solid tumors. Clin Cancer Res. 2013 Jul 15; 19(14):3996–4007.
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]. With respect to safety, higher dosing cohorts (cohort 5 through cohort 7) demonstrated a propensity to elicit transient fevers, with rare grade 3–4 pyrexia being reported. Overall, all patients tolerated infusions and most adverse reactions were managed with conservative measures [19 Brenner AJ, Cohen YC, Breitbart E, et al. Phase I dose-escalation study of VB-111, an antiangiogenic virotherapy, in patients with advanced solid tumors. Clin Cancer Res. 2013 Jul 15; 19(14):3996–4007.
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]. As with most biotherapy, a maximum tolerated dose was not reached. Cytokine levels (i.e. interleukin-6) were monitored and did not suggest a predisposition for cytokine release syndrome [19 Brenner AJ, Cohen YC, Breitbart E, et al. Phase I dose-escalation study of VB-111, an antiangiogenic virotherapy, in patients with advanced solid tumors. Clin Cancer Res. 2013 Jul 15; 19(14):3996–4007.
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]. With respect to treatment response, patients in cohort 6 and cohort 7 demonstrated stable disease on days 28 and 56 more frequently compared to their counter parts in lower dosing cohorts. Median OS was significantly longer in cohort 7 when compared to all other cohorts (median OS not reached vs. 173 days, respectively; p = 0.0098) [19 Brenner AJ, Cohen YC, Breitbart E, et al. Phase I dose-escalation study of VB-111, an antiangiogenic virotherapy, in patients with advanced solid tumors. Clin Cancer Res. 2013 Jul 15; 19(14):3996–4007.
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In 2015, an early phase clinical trial was presented at the Society of Neuro-Oncology annual meeting, which highlighted the safety and efficacy of VB-111 in patients with recurrent GBM. In this phase 1/2, multicenter, dose-escalation study, VB-111 was administered intravenously to 62 patients at 1 × 10e12 VP and 1 × 10e13 VP, of which 46 received repeat doses of 1 × 10e13 VP administered every 2 months. Initially, VB-111 treatment was administered until further progression, thereafter it was discontinued and patients received BEV SOC (limited exposure cohort, n = 22). The protocol was then amended to allow further exposure to VB-111; thus, upon progression, BEV 10 mg/kg biweekly was added and combined with VB-111 bimonthly (continuous exposure cohort, n = 24) [20 Brenner A, Cohen Y, Vredenburgh J, et al. Phase 2 study of VB-111, an anti-cancer gene therapy, as monotherapy followed by combination of VB-111 with bevacizumab, in patients with recurrent glioblastoma [abstract]. In: 20th Annual Scientific Meeting and Education Day of the Society for Neuro-Oncology; 2015 Nov 19–22; San Antonio, TX. Neuro-Oncology 17: v45–v54, 2015.
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The investigators demonstrated that there was a statistical improvement in OS among the continuous exposure cohort (16 months), compared to the limited exposure to VB-111 (8 months, p = 0.048). The study also revealed that the combination of BEV and VB-111 can be safely administered in the setting of progressive GBM [20 Brenner A, Cohen Y, Vredenburgh J, et al. Phase 2 study of VB-111, an anti-cancer gene therapy, as monotherapy followed by combination of VB-111 with bevacizumab, in patients with recurrent glioblastoma [abstract]. In: 20th Annual Scientific Meeting and Education Day of the Society for Neuro-Oncology; 2015 Nov 19–22; San Antonio, TX. Neuro-Oncology 17: v45–v54, 2015.
]. A large phase 3 trial is currently ongoing (discussed below).
6. Future directions
The use of VB-111 in the setting of high-grade glioma is currently being investigated in a phase 3, randomized, controlled, open-label, industry-sponsored clinical trial (NCT02511405). The study (also known as the GLOBE trial) is designed to assess VB-111 with or without the addition of BEV in patients with first or second progression of GBM. Within the experimental arm, VB-111 will be administered intravenously at a dose of 1 × 10e13 VP every 2 months along with BEV every 2 weeks. The control arm will only receive BEV. The primary outcome will be OS, with PFS and tumor response representing secondary end points [21 A phase 3, pivotal trial of VB-111 plus bevacizumab vs. bevacizumab in patients with recurrent glioblastoma (GLOBE). [updated 2016 Mar 16; cited 2016 Mar 23] Available from:
http://clinicaltrials.gov/ct2/show/NCTNCT02511405
7. Conclusion
VB-111 is a novel agent in a market that is dominated by FDA-approved small-molecule inhibitors and monoclonal antibodies targeting angiogenesis. The mechanism of action has been demonstrated to be safe and potentially effective in early phase clinical trials. Its development will hopefully lead the way to more vector-mediated genetic alteration of the neoplastic process via disruption of angiogenesis. Further clinical investigation of this exciting new means of targeting cancer is warranted.
8. Expert opinion
High-grade gliomas are characterized by a propensity to develop an intricate, yet disorganized array of blood vessels. These vascular networks potentiate growth of the tumor and have been the focus of several different modalities of treatment. Most notable of these agents is BEV, with its suggested efficacy being most evident in the recurrent setting; however, its impact on OS has been thrown into doubt. This lack of a survival benefit possibly stems from the intrinsically redundant nature of angiogenesis; in that, multiple pathways of blood vessel formation allow the tumor to escape a single agent that targets proliferation. Therefore, there is an unmet need to circumvent these mechanisms of escape and to fully take advantage of inhibiting angiogenesis in high-grade gliomas.
VB-111 represents a novel approach to tackling the issue of antiangiogenic escape mechanisms and potentially improving survival parameters in patients with high-grade gliomas. Using a genetically engineered viral construct, VB-111 is based on a nonreplicating adenovirus vector that preferentially targets tumor-associated endothelial cells. The viral payload it carries is a Fas-chimera transgene, which is regulated by a unique tissue-specific promotor region (PPE-1-3x). The activation of this promotor region is dependent on the elevated rate of angiogenesis intrinsic to high-grade gliomas. Upon transcription of the transgene, a chimeric receptor is expressed on the cell surface; of which, the extracellular domain is a human TNF receptor, and the transmembrane and intracellular domain is composed of Fas. The interaction of TNFa with the extracellular component leads to a Fas-dependent caspase-mediated apoptotic cascade. As demonstrated in preclinical animal models, this mechanism effectively starves the tumor of its blood supply and improves survival.
Early phase clinical data suggest that VB-111 is safe and can be well tolerated by patients with high-grade glioma. A maximum tolerated dose was not reached and the clinical behavior of the virus suggested that patients may derive the most benefit at higher doses. Additionally, results presented by Brenner et al. at the 2015 Society for Neuro-Oncology meeting suggested that the addition of BEV to continuous VB-111 therapy can be well tolerated and may provide a survival advantage. Thus, the GLOBE trial will help to further corroborate these findings in a large, randomized, phase 3 setting, where VB-111 is paired with or without BEV in patients with recurrent GBM.
Viral-mediated treatment of malignancies is an exciting field of research that may potentially circumvent many of the challenges posed by cancer’s intrinsic mechanisms of resistance to conventional therapy. VB-111 represents one such modality that is being actively investigated in high-grade gliomas. As evidenced above, VB-111 can be combined safely with other antiangiogenic therapies. It is intriguing to consider the combination of VB-111 with standard cytotoxic agents, or even with the combination of immunotherapy. In the rapidly evolving field of oncology, the latter combination may prove to be the more likely scenario that may be examined in future clinical trials. Thus, the onus will be to demonstrate that unleashing a host immune response against highly vascular malignancies can be safely done in the setting of TNFa-mediated endothelial cell apoptosis; a consideration especially important in the setting of those patients who develop fevers while receiving VB-111 compared to those that do not. With respect to the latter group of patient, a possible hypothesis to consider is whether immunotherapy may improve response rates in this population.
Overall, VB-111 represents an important step forward to using genetically engineered biotherapy for the treatment of high-grade gliomas. Its safety, efficacy, and comparative benefit warrant further exploration in large clinical trials.
Declaration of interest
VBL reviewed and agreed on the publication of this manuscript, also providing access to Figure 1 for the paper. KB Peters has acted on the advisory board for Novocure and Agios. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
rGBM is a tough nut to crack. Not many will invest in VB-111 because of this, and short sellers will sell based on this statistic. The odds are HEAVILY stacked against VB-111 being successful (in extending OS). If prior drugs have had success against rGBM then I think you'd see the stock at around $10-15 based on potential.
If VB-111 is effective, it'll be the first one to claim that it can improve survival.
Even avastin cannot claim this - "Currently, no data have shown whether or not Avastin improves disease-related symptoms or survival in people with rGBM."
Some interesting tidbits at the end of the press release:
"The new facility will also include the company’s headquarters, discovery research and clinical development. VBL intends to operate and relocate to the new site in the second half of 2017.
VBL said that future commercial supply of VB-111 will likely involve a complementary source of supply, probably via a Contract Manufacturing partner in North America, although those plans have not yet been set."
1) Moving HQ
2) Expanding operations
3) Future NA manufacturing partner
All positive indicators.