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2-3% drop = "market/institution believe they fail in the phase 3"? wow, ok ....
Comparison to celldex and avastin.
2016 video but in case anyone missed it:
MIXiii Biomed 2017 Program
Prof. Dror Harats, MD, CEO, VBL Therapeutics: "Viral Immune Oncology"
http://kenes-exhibitions.com/biomed2017/program-overview/
Talk about "a rock and hard place" ... 0% chance to fail vs 0% improvement in mOS for rgbm.
Unfortunately, one has been established by many failed phase 3s. The other is based on 3 successful phase 2 results. And remember, those trials that moved to phase 3 did so because they had successful phase 2 results.
Still, I believe that VB-111 will be successful but I'm not as confident as oren.
Thanks, value. That does further confirm the pricing.
Hope we get to talk about pricing one day because that would mean the drug has made it to market!
Oren, I leave the pricing to the market. On one hand, companies spend millions/billions to research and get a drug to market. They're not going to do it if the risk/reward is not there.
Just look at VB-201. They spent millions researching it but it failed in psoriasis. VBL (and its investors) is getting nothing (so far) back for the millions it spent. Numerous other examples of drug companies not getting a return on their investments because the drug failed. So when a drug does make it to market, I do understand the rational for some of the pricing. The price factors in such things as profits, funding for future research and failed investments ... not to mention other SG&A expenses.
What Shkreli did, though, was unethical.
Exactly. I feel the same way.
By the way, if/when VB-111 gets marketed, this comment gives you an idea of how it'll be priced:
“It will not be a very cheap drug,” Erez Feige, the company’s VP of business operations, said in an interview, adding that “we believe it should be in the range of” Merck’s Keytruda, which rings up at $150,000 per year. But “if the drug is really improving overall survival,” he said, “there’s justification to pay for that.”
http://www.fiercepharma.com/pharma/no-scandal-here-say-rare-disease-drugmakers-as-pricing-scrutiny-lands-their-doorstep
I am staying until at least after the interim ... most likely longer.
Here you go, Oren: http://www.abstractsonline.com/pp8/#!/4277/presentation/151
Interesting that Avastin achieved 10 months mOS in this trial. It historically has achieved 8 months (32 weeks).
Nivo's 9.8 months (39 weeks) would have beaten Avastin's 32 weeks but in this case, Avastin performed better than usual. VB-111's mOS was 59 weeks in Ph2 so that is still significant if it is repeated in Ph3.
This is the takeaway from ASCO:
"Spider diagrams demonstrate similar rapid tumor growth in both LE and TThP cohorts during the VB-111 monotherapy period (local site data; median % increase (MPI) per 30d: 14.8 vs 14.1, p = 0.98). In the TThP cohort, growth was attenuated after the 1stprogression, compared to the preceding VB-111 monotherapy period (MPI: 0.6 vs 14.1, p = 0.0032); responses were seen, including 2 complete responses (CR), one patient remaining in CR over 3 years. A similar attenuation was seen in central lab tumor measurements. "
Remember, this is a small company with limited resources. They are not a large pharma that can throw bodies and millions to do another trial. This may be the reason why we see some delays and why the company opted for a faster path by not doing a SPA for ovarian.
davidal66 ... since the company has been through a SPA with rgbm, I think they know the pros and cons about doing it. I suspect they have more confidence in the ovarian results and therefore, need less assurances from the FDA. Not doing a SPA also cuts down on time and costs.
This site sums it up well:
"However, the SPA process can often take several rounds of FDA review before agreement is reached and the FDA may require a more robust trial design than what would have otherwise been considered adequate, which could result in unnecessary delays and increased costs. As with all aspects of drug development, a sponsor should carefully weigh their priorities before entering into an SPA agreement with the FDA."
http://camargopharma.com/2017/04/special-protocol-assessment-important-drug-development-program/
Value ... I thought about the buyer angle as well. It would explain some of the delays ... and perhaps even why they opted not to do the SPA.
But at this point, the company is so close to a key milestone that I am less concerned about what happens in 4Q17 or 2018.
In the latest conference call:
1) Dror clarified the interim date to late Q3 and said it's driven by the 12-month follow up on half of the patients. That date is in Q3 and since it takes a few weeks to analyze the data, the announcement will be in late Q3. But he also said that the events were occurring to what they expected.
2) Confirmed ph3 ovarian in 2H17. FDA offered a SPA but company declined. Already picked CRO and will provide more info later. Like rGBM, not doing European countries. More color: "We already had a discussion with agency in December of 2016, and we already got the green light on the protocol and the green light of doing a Phase III where the endpoint is survival; so all of this has been done. What we will have in second half of ’17 is actually start recruiting patients."
3) Confirmed launch study of combo with a PDL-1 blocker in lung cancer by EOY17 .. and later said that first trial will be after the data in 1Q18
4) Confirmed presenting new data at ASCO "that VB-111 in destroyable tumor regression and attenuation of tumor growth in recurrent GBM using individual Phase II patient data". This data may explain the driver behind the increase in OS.
5) Confirmed new production facility will be operational 4Q17
6) Said DSMC focussed primarily on safety but also factored in efficacy
7) Not doing ph3 for thyroid but said that if VB-111 is on the market and thyroid patients need the drug then it could be available for them without a need to do a full ph3 for thyroid. Nice to cross that bridge when that happens.
Personally, I see the company making positive progress. The next 3-5 months will be significant.
It's still early but I thought this was a good interpretation of the results.
=========
An important observation from our pre-clinical data in the LLC model was that the combination of VB-111 at a dose of 10^9 viral particles (VPs)/mouse, which is equivalent to the human therapeutic dose, with a PD-L1 blocker, yielded a tumor burden reduction similar to treatment with 10^11 VPs/mouse, a 100-fold higher dose ... Therefore, a combination with a checkpoint inhibitor may achieve much better anti-tumor activity than VB-111 alone
=========
Agree wcopeland. Mid-2017 in my mind is June to July or can be expanded to May to August. Now with the company changing to Q3 (which is a positive) it helps narrow down the range to July to August.
DSMC, Q3 ... all positive signs so far ...
It does seem the company is more active (with all the recent news release) and upbeat. Hopefully that's a sign that things are going as planned.
Another (positive) seekingalpha article about VBLT. Vultures and sharks ...
https://seekingalpha.com/article/4070019-vascular-biogenics-initiating-coverage-first-price-target-13
davidal66, wcopeland - I have a private google doc that I can share with you.
It contains names and links of VB-111 related stuff. I don't want to discuss that information on a public forum so if you want to discuss these things in a private space, I can share with you the document and you can read/edit/add your stuff as needed.
Let me know if you're interested by sending me an email at gr081727364453@gmail.com
Dror's compared avastin vs VB-111 by saying:
"Avastin blocks one anti-angiogenic factor (VEGF), while the tumor cells have redundancy and can overcome VEGF blockade by secreting one or more alternative pro-angiogenic factors. The MOA of VB-111 is completely differentiated from Avastin or TKIs, and is not limited to a certain factor or mutated pathway. In fact, in ovarian cancer, we have seen responses with VB-111 even post failure on Avastin and TKIs, including in women whose tumors were platinum-resistant/refractory. The added value coming from VB-111’s immune effect further enhances its anti-tumoral activity. Currently, there are very limited options for recurrent-GBM or platinum-resistant ovarian cancer patients, especially treatments that can prolong patients’ survival."
This is what I have consistently heard. Don't recall him saying one is general and the other is specific.
Interesting difference between avastin and VB-111. Did Dror discuss this difference in past presentations?
"For those curious, Avastin works by inhibiting blood vessel formation throughout the whole body. Its effect is systematic because it consists of antibodies that attack a protein necessary to build blood vessels as if that protein were a pathogen. Avastin slows the formation of new blood vessels everywhere; VB-111 gets new blood vessels to kill themselves in the tumor microenvironment."
It's from seekingalpha so I would not rely on the information unless confirmed independently:
https://seekingalpha.com/article/4067735-vascular-biogenics-microcap-potential-blockbuster-cancer-therapy-phase-3
Oren, for the record, I will take either 99% or 100% chance.
Once VB111 can prove itself in rgbm then many doors will open.
*no grammar police on this board, value* don't worry about it
Regarding your question, I don't think they will announce it at ASCO, which is good. The later the interim report, the better, imo. They will present new data for phase 2 at ASCO and that's about it.
I think the interim news will drop around July/August. Stay tuned!
Found a thread called "just avastin" on inspire. Worth a read since many of those symptoms are seen on patients using avastin + vb111/some other combo
Something to keep in mind is that some of those effects could be coming from avastin. If you search for some of those symptoms and avastin, you'll come up with articles/forums that talk about avastin and similar symptoms. Plus, most (all?) of these patients have had prior treatments and their health has been degrading.
Makes me wonder how well vb111 would do as frontline, with healthier patients.
You're right. I forgot that it was mentioned on the last call:
But I expect that we are going to present in the next coming months more data on our MOSPD2 at AACR, more data on the combination of VB-111 with checkpoint inhibitors, preclinical work that we were doing showing efficacy, and we intend to present individual data on our GBM trials, including spiders [ph], which hopefully will speak for themselves, and some more data that’s actually showing the immune mechanism of VB-111, so that’s planned for the next coming months until mid-June.
Guess/hope on "new" data at ASCO?
Because of the low number of patients, I think any data (no matter how amazing) is going to need further exploration. And perhaps this will set the stage for future exploration/partnership.
1) Fever: I think this one is the most obvious. Perhaps they will show data on patients with fevers vs other group
2) Prior treatment: Perhaps patients with prior treatment (like PDL1) showed different results vs other group
3) OS: Perhaps there are some on VB-111 with significant OS data
I think the ASGCT one will be more significant because it may reveal more info on the combo therapy and partnership.
ASCO is just a presentation of ph2 rgbm.
Yes and no. Yes, they did have choice. But none of them pick the avastin alone. It sounds like the first 22 patients were given avastin alone. Then, the remaining 24 were given a choice. This was not random, but it was also not a selection process to pick the healthiest patients for VB111.
Here are the details from 20-F (as a rule, SEC filings are much more detailed than news releases):
In order to explore the efficacy of the combination regimen, in March 2015 we performed a current interim analysis which compared patients who received bevacizumab alone after progression on VB-111 monotherapy, in a “sequential regimen”, to those who after progression on VB-111 monotherapy received bevacizumab combined with continued VB-111, termed “combination regimen”.
As of March 24, 2015, our interim Phase 2 data include 46 patients with rGBM. VB-111 monotherapy was discontinued upon progression in 22 patients who were then treated with bevacizumab alone. The remaining 24 patients, upon disease progression on VB-111 monotherapy, could elect to receive further treatment with VB-111 in combination with bevacizumab. Twenty three have received combined therapy; one patient remains stable on VB-111 monotherapy at 424 days. VB-111 in combination with bevacizumab demonstrated a statistically significant improvement in overall survival, with median overall survival of 414 days, compared to 235 days in patients on VB-111 followed by bevacizumab alone (p=0.05). Although these data are not fully mature, they are statistically significant.
Patient selection criteria is key, imo. Dror has stated that they did not hand select ph2 patients to improve results because that would set the drug up for failure in ph3. It was his response to questions regarding why some ph3 rgbm trials were failing.
ph2 and ph3 are similar in that they did compare avastin alone and avastin+vb111.
Phase 2 and 3 are different:
ph2) Single-Arm Open-Label
https://clinicaltrials.gov/ct2/show/NCT01260506
In the first stage of the study, patients were treated with VB-111 alone. Upon disease progression, patients entered the second stage of the study, in which they received either Avastin alone as standard of care (limited exposure cohort) or VB-111 in combination with Avastin (continuous exposure cohort).
ph3) Randomized, Controlled, Double-Arm, Open-Label, VB-111 Combined With Bevacizumab vs. Bevacizumab Monotherapy
Agree on all points, davidal66. I will add ...
DSMC did not recommend to end the trial due to efficacy - so it's not all bad.
The confidence in the timing tells me 1) they are very close to the number of events or 2) they have hit the number of events and will report based on the 12-month follow up of 50%. But we don't know what's driving the numbers: Avastin or VB-111.
Lots of unknowns and news is dropping at a faster (unpredictable) rate. I also noticed that there has been less chatter about VB-111 - good or bad.
Remember, the interim is triggered when 105 events have occurred or 50% of the patients have had 12-month follow-up, whichever comes later. The key is to know when 50% of the patients have been enrolled so we can estimate the 12-month follow-up timeframe. As far as I know, that information is not available.
What we know is:
August 2015: first patient dosed
December 2016: enrollment completed
Somewhere in those 16 months, 50% of the patients were enrolled ... but we have to account for the dropouts to obtain the 12-month follow-up. Let's assume 50% were enrolled after 10 months (keep in mind there were only a few locations at first). Add 1 month for the dropouts.
So that brings us to July 2016. 12-month follow-up would hit exactly in June/July in this case.
If the interim is triggered by the 12-month follow-up then that mean the 105 events have occurred. This also makes sense since they seem to be confident on the timing of the interim.
Agree. That's the way I see it, memeil26.
VB-111 is safe. Prior trials indicated it would be and this latest information confirms it.
Prior trials have shown that it's effective. I don't think the DSMC indicates how effective it is but the DSMC didn't stop it due to efficacy. If avastin performs to its historical numbers, the confirmation of mid-year interim is also a positive signal, imo.
That's how I'm reading it.
Here's the link from FDA. Seems to say the same thing.
https://www.fda.gov/OHRMS/DOCKETS/98fr/01d-0489-gdl0003.pdf
So does this positive DSMC review mean there was no lack of efficacy? hmmmmm
============
I. REVIEW OF INTERIM ANALYSES
Clinical research study/ies that are monitored by the DSMC may contain stopping rules for excessive toxicity or lack of efficacy. Whenever an interim analysis is performed to ensure that no study defined stopping rules have been met, a copy of the analysis must be forwarded to the DSMC. The DSMC will acknowledge the receipt of the analysis and discuss the results at its next regularly scheduled meeting.
Huge news release - 2nd DSMC review good to go. No AE concern!
Very interesting quote: “Based on enrollment trends and events that triggered the DSMC review, we currently expect the GLOBE Trial interim analysis to occur in mid-2017, and top-line results from the full dataset to be available in early 2018.”
Sounds like events are occurring on schedule. Hopefully, data supports findings in phase 2.
http://ir.vblrx.com/phoenix.zhtml?c=253311&p=irol-newsArticle&ID=2263414
VBL Therapeutics Announces Positive DSMC Review in Phase 3 GLOBE Trial Investigating VB-111 in rGBM
TEL AVIV, Israel, April 20, 2017 (GLOBE NEWSWIRE) -- VBL Therapeutics (NASDAQ:VBLT), today announced that the Independent Data Safety Monitoring Committee (DSMC) met to conduct its second safety review of the Phase 3 GLOBE Study investigating ofranergene obadenovec (VB-111) in recurrent glioblastoma (rGBM). The DSMC is an independent multidisciplinary group that conducts detailed reviews of un-blinded study data, discusses potential safety concerns and provides recommendations regarding trial continuation. The committee reviewed the GLOBE safety data collected through a cutoff date in March 2017 and unanimously recommended that the study continue as planned.
“We are pleased with the outcome of the DSMC,” said Dror Harats, Chief Executive Officer of VBL Therapeutics. “Based on enrollment trends and events that triggered the DSMC review, we currently expect the GLOBE Trial interim analysis to occur in mid-2017, and top-line results from the full dataset to be available in early 2018.”
The Phase 3 GLOBE study in rGBM is comparing VB-111 in combination with Avastin® (bevacizumab) to Avastin alone and has recruited 256 patients in the US, Canada and Israel. The study is proceeding under a Special Protocol Assessment (SPA) granted by the FDA, with full endorsement by the Canadian Brain Tumor Consortium (CBTC). VB-111 has received orphan drug designation in the United States and Europe and was granted Fast Track designation by the FDA for prolongation of survival in patients with glioblastoma that has recurred following treatment with standard chemotherapy and radiation.
Good read about anti-angiogenesis and gbm.
http://www.medscape.com/viewarticle/582339
=========
Since angiogenesis is virtually absent in normal adults, antiangiogenic therapy is more tumor-specific and yields a low toxicity profile. Different antiangiogenic strategies have been developed: inhibition of proangiogenic factors and/or receptors and/or downstream cell signaling; inactivation of ECs; and inhibition of cellular adhesion molecules and/or ECM remodeling. Inhibitors of angiogenesis are separated into endogenous inhibitors, such as angiostatin, trombospondin or IFN-a; and natural or synthetic inhibitors, such as THD, antibodies against angiogenic growth factors or inhibitors of tyrosine kinase receptors.
No clear benefits for patients have been reported regarding the use of single antiangiogenic drugs. Interestingly, the levels of angiogenic molecules in circulating blood from patients with tumors have been shown to increase significantly in response to antiangiogenic treatment.[103] The mechanisms involved in this phenomenon are not known. The role of the third compartment (i.e., pericytes, microglia and astrocytes) as well as endothelial and tumor cells remains unclear. Furthermore, several mechanisms are involved in angiogenesis, and the targeting of one molecule or pathway may lead to the increased activity of other pathways, which may then sustain angiogenesis. It seems likely that a combination of these antiangiogenic agents with chemotherapy seems to be more efficient.
Antiangiogenic therapy has been demonstrated to represent a promising novel approach to the treatment of malignant brain tumors. It seems likely that a combination of antiangiogenic agents with other cytotoxic therapies will be required to achieve maximal efficacy. Antiangiogenic compounds are not expected to reduce the tumor burden but, rather, to exert a cytostatic effect. A crucial issue is, therefore, the search for end points and surrogate markers as indicators of biological response and anti-tumor activity.
Since avastin's OS is 32 wks (8 mos), an improvement of another 12 wks (3 mos) ... an improvement of almost 40% ... would be very significant. Avastin's patent expiration would enable the biosimilars to offer a cheaper alternative if patients want to take both VB-111 and avastin biosimilar as a combo therapy.
I think that the majority of the patients, when given an option to extend OS by 40%, would pick that option.
If all this plays out ... how much would Roche pay? Well, avastin and its biosimilars all do not extend OS. VB-111 would be the only drug that can make the claim of improving OS. If effective in rGBM, VB-111 would most likely be effective in other solid tumors. So we're talking about a very big number for peak sales. Definitely in the billions and the buyout price would have to be multiples of peak sales.
Nice to day dream but it will all get clearer in a few months.