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Yup, avastin's patent is expiring in 2019 and there are 4 biosimilars in phase 3. Amgen's biosimilar is in BLA. They all want a piece of that $7 billion pie. VB-111 being in phase 3 really doesn't threaten Roche because of the timing of the patent expiration.
http://www.nature.com/nrd/journal/v16/n3/fig_tab/nrd.2017.36_T1.html
Now, if VB-111 does significantly better than Avastin then that would be a different story. Amgen, Pfizer, Roche, AZ ... all potential partners/buyers.
Agree that rGBM is very tough .. but on the bright side for VB-111 interim, the bar is set very low (avastin). Still, avastin is still around because there is nothing else out there to replace it. One good thing about VB-111 is that it is similar to avastin: it is also an anti-angiogenic. It's the only approach that has been effective. As we have seen, many other approaches have had promising ph2 results only to fail in ph3.
It's not bad that a useless drug has peak sales of $7 to $9 billion. I wish VB-111 becomes that "useless" ... lol.
All kidding aside, one thing to note is that avastin's US patent is expiring in 2019 so the clock is ticking for Roche. If VB-111 gets positive interim then I can see Roche and AZ taking a very strong look at VBL.
This is why the stock price / market cap is so low.
Many promising drugs but nothing has cracked the glioblastoma nut. Avastin is still the SOC for rGBM.
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>> On April 3, 2017, Bristol-Myers Squibb announced that the CheckMate-143 Phase III trial, which evaluated Opdivo versus Roche’s Avastin (bevacizumab) in patients with recurrent GBM, failed to meet its primary endpoint based on survival benefit.
>> GlobalData considers Avastin as a weak comparator as it has never shown survival benefit and is not even approved as GBM therapy by the European Medicines Agency. However, Avastin remains the first choice for recurrent GBM in all major markets—through off-label use in Europe—due to the lack of therapeutic options for GBM patients.
>> Last year, another immunotherapy agent failed in the newly diagnosed setting, Rintega, after Celldex announced the termination of the ACTIV Phase III trial assessing its EGFRvIII peptide-based cancer vaccine in newly diagnosed GBM patients.
http://www.pharmaceutical-technology.com/comment/commentuncertainty-grows-for-immuno-oncology-therapies-in-glioblastoma-multiform-5786007/
Here is a good summary of what to expect for interim futility analysis:
BACKGROUND:
Interim analysis of Phase III trials typically includes testing for both efficacy and futility. Futility testing is commonly performed on the primary outcome at very low levels (e.g., one-sided alpha=0.0025) at one or two times before final analysis. When overall survival is the primary outcome and events accrue slowly, and if a suitable intermediate endpoint is available, then using this endpoint for interim futility testing may yield a higher probability of stopping early for futility in the absence of any treatment effect.
https://www.ncbi.nlm.nih.gov/pubmed/18283075
Recently, Argos (dendritic) failed their interim futility while Mesoblast passed.
Argos:
the IDMC recommended it be stopped because a statistically significant survival benefit was not being shown in the trial arm relative to control, and in their recommendation, they did not see a chance where such a benefit could be met if the trial was allowed to continue until 100% of events (patient deaths) occurred in both arms.
https://seekingalpha.com/article/4050153-argos-therapeutics-store-adapts-failure
Mesoblast:
The dataset for the interim analysis includes non-fatal and terminal cardiac events from the first 270 of the anticipated 600 patients to be included in this ongoing trial. The IDMC will review and interpret the results of the interim analysis and provide recommendations shortly.
https://globenewswire.com/news-release/2017/03/31/947518/0/en/Independent-Data-Monitoring-Committee-Initiates-process-for-Interim-Analysis-of-Mesoblast-s-Phase-3-Chronic-Heart-Failure-Trial.html
LifeSci summary on KOL - pretty good read:
https://www.baystreet.ca/articles/research_reports/lifesci/NovelImmuno041117.pdf
If MOSPD2 is targeted as a treatment for cancer, depleted macrophage levels can be managed with Amgen’s (NasdaqGS: AMGN) Neuopogen (filgrastim), which is able to boost white blood cell counts. Because of this, MOSPD2 could be a viable cancer target since the damage caused to non-cancer cells, being macrophages, can be treated. The function of MOSPD2 was not previously well known, but through a series of studies investigating the mechanism of monocyte migration, VBL has so far identified that it has the following characteristics:
? Expressed on the cell surface of monocytes.
? Involved in cell migration and metastasis, making it an attractive target.
? Protein is expressed in many types of solid tumors.
? MOSPD2 correlates with tumor invasiveness in breast cancer
Agree on all points, wcopeland, including how Dror comes off as being confident/excited and enjoying his discussion with other scientists. Excellent summary - thank you.
Btw, regarding potential partners "Currently BMS, Merck & Co. and Roche have PD1/PD-L1 modulators on the market. Astra Zeneca’ s PD-L1 blocker durvalumab is expected to reach the market this autumn". As I mentioned in an earlier post, Ramy Ibrahim has strong connections with AZ and with AZ being late to the party, I'm beginning to lean towards AZ as the potential partner.
http://european-biotechnology.com/up-to-date/news-and-stories/news/fda-approves-mercks-avelumab-in-mcc.html
Listen to the KOL (I posted link on another reply) and let me know what you think. There is also a presentation that you can download.
Register for KOL here: http://lifesci.rampard.com/20170406/reg.jsp
Biocentury article on MOSPD2 as referenced in the KOL.
https://www.biocentury.com/bc-extra/clinical-news/2017-04-05/mospd2-linked-breast-cancer-metastasis
I really liked what was discussed in the KOL. Dror sounded very confident and excited. Very innovative approach to treating solid tumors.
VB-111 discussed in KOL was also interesting. "If we meet the primary endpoint (survival) it should be the only trial to put this drug on the market."
Known but worth mentioning again .. Thyroid trial: patients have exhausted every treatment in thyroid ... tail: 40% alive after 3.7 years.
Interim results estimated in mid-year .. "later it gets the better for us ... means not enough patients died." Top line data end of year or beginning of next year (again, later the better).
By combining therapy (PD-L1) can maximize effect of VB-111. <<- I think we found the other therapy for the combo trial.
I listened to the KOL. Definitely very interesting. MOSPD2 is a new target. In the summary he said, "VBL is developing mAbs and CAR-T for targeting of MOSPD2-positive cancer cells."
MOSPD2 expressed on cell surface of monocytes ... and abundantly in many solid tumors. Not expressed in other cells in the body - only monocytes. Correlates with signaling in monocyte cells. Huge opportunity to block the migration of monocytes.
I think they're on to something ... interesting indeed.
Great summary: Phase 3 GBM trials
Nivo just bowed out. GBM is a very tough nut to crack. There are limited options. If VB-111 can improve OS then it would be met with huge demand.
link:
https://blog.braintumor.org/potential-glioblastoma-treatments-entering-the-pivotal-phase-of-evaluation/
Phase III Clinical Trials in GBM with Novel Investigational Agents
Active
A Phase 3, Pivotal Trial of VB-111 Plus Bevacizumab vs. Bevacizumab in Patients With Recurrent Glioblastoma (GLOBE)
A Study of the Effectiveness and Safety of Nivolumab Compared to Bevacizumab and of Nivolumab With or Without Ipilimumab in Glioblastoma Patients
Study of a Drug [DCVax®-L] to Treat Newly Diagnosed GBM Brain Cancer
P2/3 Randomized Study of Toca 511 & Toca FC Versus SOC in Subjects Undergoing Surgery for Recurrent GBM/AA
Recruiting
Phase 3 Randomized, Double-blind, Controlled Study of ICT-107 in Glioblastoma
Study of Nivolumab Compared to Temozolomide, Given With Radiation Therapy, for Newly-diagnosed Patients With Glioblastoma
Disulfiram in Recurrent Glioblastoma
Not Yet Recruiting
A Phase II/III Study of High-dose, Intermittent Sunitinib in Patients With Recurrent Glioblastoma Multiforme
Phase II/III Trial of CCRT With or Without JP001 for Newly Diagnosed GBM
The Effect of Escitalopram on Mood, Quality of Life and Cognitive Functioning in Glioblastoma Patients
If I understand their ph2 correctly they did not design it like their ph3 (vs avastin).
If the ph3 trial design was similar to VB-111 then I'm not too surprised that it failed due to its ph2 single-agent results:
============
In the single-agent nivolumab arm, the median progression-free survival (PFS) was 1.9 months (95% CI, 1.3-6.5). The median PFS was 2.1 months with N1/I3 (95% CI, 0.5-3.0) and 2.4 months with N3/I1 (95% CI, 1.4-4.7).
http://www.onclive.com/conference-coverage/asco-2016/nivolumab-effective-in-early-stage-study-for-glioblastoma#sthash.ZudtaGVM.dpuf
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This is why Dror kept emphasizing that VBL ph2 and ph3 are very similar (identical?) in design and recruiting standards. Many companies get cute with their ph2 trials (either in design or recruiting, or both) but VBL did not do that.
wcopeland: if you're referencing this part "Positive interim gives the company more leverage", then the leverage that VBL would gain is getting better terms from its (larger) partner.
It doesn't matter if VB-111 is not part of the partnership. A successful VB-111 would enable VBL to have more options and thus, demand better terms.
After hour is up to 6.65. Only a few hundred shares traded but it is strange that someone would buy it at a premium.
Any guess on the partner? Roche? AZ? BMS? Merck?
davidal66: agree on the timing. I'm thinking some time in Q4, after VB-111 interim. Positive interim gives the company more leverage.
KOL is coming up. Will be interesting to hear the discussion.
wcopeland: they have not mentioned when they'd initiate a checkpoint trial although Dror has mentioned it a few times already. Just like the partnership potential. He has mentioned it in prior conferences but this last time ... the way he said it ... it seems more imminent.
"BEFORE they get final readout of Ph3 rGBM study. A partnership helps them mitigate any bad news from that study". It would be shocking if the interim is positive and the final readout results in something different.
Partnership can be a good thing for a company with limited funds and the need to do multiple trials. Let's wait and see what transpires. Any guess as to when this potential partnership will be announced?
Had no idea they completed 3 ph2 studies for vb-201.
http://ir.vblrx.com/phoenix.zhtml?c=253311&p=irol-newsArticle&ID=2259170
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VBL has studied VB-201 in five Phase 1 studies and three Phase 2 studies, some of which included patient populations known to have high rates of metabolic syndrome (e.g. psoriasis). In a retrospective analysis of liver enzyme tests performed for subjects dosed with VB-201, the Company identified a statistically significant time- and dose- dependent reduction of alkaline phosphatase (ALP) blood levels in patients treated orally with VB-201, which was reversed during a 4-week follow-up period after the patients completed the study.
Yeah, I heard that. VB-201 w big pharma, ph 2. Safe in over 600 patients.
Sounds good. I look forward to Thurday's KOL.
Agree oren. Also the reason why recruiting went well - many doctors (and patients) were demanding it.
Key Opinion Leader Ramy Ibrahim, MD from the Parker Institute, will discuss new targets and immunotherapeutic approaches to oncology at a breakfast meeting being held in New York on April 6 at 8 am
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Register here: http://lifesci.rampard.com/20170406/reg.jsp
Worth a listen. The guy has AZ connection.
http://www.parkerici.org/media/2016/parker-institute-for-cancer-immunotherapy-adds-key-leader-to-drive-clinical
Parker Institute for Cancer Immunotherapy Adds Key Leader to Drive Clinical Research Efforts
SAN FRANCISCO, June 15, 2016?—?The Parker Institute for Cancer Immunotherapy has recruited Ramy Ibrahim, M.D. as its new Vice President, Clinical Development. Ramy was most recently employed by AstraZeneca where he led the clinical team developing multiple immunotherapies. Ramy Ibrahim is a trained medical oncologist, who conducted bench and clinical immunotherapy research at the National Cancer Institute in Bethesda, MD.
“Ramy has been a pioneer and leader in cancer immunotherapy and will lead the Parker Institute as we grow our collaborative clinical enterprise with our institutional leaders at Memorial Sloan Kettering Cancer Center, Stanford Medicine, the University of California, Los Angeles, the University of California, San Francisco, the University of Pennsylvania and The University of Texas MD Anderson Cancer Center.” said Jeffrey Bluestone, CEO and President, Parker Institute for Cancer Immunotherapy.
Prior to joining the Parker Institute, Ramy served first as Senior Medical Director and most recently, the Clinical Vice President, Immune-Oncology, Global Medicines Development at MedImmune/AstraZeneca where he built and led the clinical team working on the registrational studies both with single drug and combination therapies. As a member of the Bristol Meyers Squib Immuno-oncology program, he served on the BMS Yervoy (ipilimumab) clinical team supporting the program from early phase II through multiple global launches of the first FDA-approved Immune Checkpoint inhibitor. In addition, he played a key role in early development for nivolumab (PD-1), PDL1, and CD137 antibody.
Throughout his career, Ramy has been involved with global cancer immunotherapy societies such as Society of Immunotherapy for Cancer (SITC), Ludwig Institute, and the Cancer Research Institute and Cancer Immunotherapy Trials Network (CITN).
That is a very interesting video!
1) VB-111 educates the immune system how to fight cancer (at 1:25). Is this new or has this been mentioned before (and I missed it)? Seems like it is a result from the fevers that developed after being given VB-111.
2) Works for ALL solid tumors (including lung). If it gets approved for rGBM ... then ovarian ... imagine the future possibilities.
I'm not too concerned if it does as well as ph2 (I hope it does or better!). As long as it works better I think it will be approved. Patients are starting to be scared/concerned to take avastin ... avastin's reward/risk profile is poor ... they will only take it as a last resort.
Yeah, I wonder if they're going to present both 201 and 703 ... looking forward to seeing what they present.
oren, it is "because at that point a trial will already be at the position that half of the patients will have at least one year follow-up" ... and as davidal said it is a futility analysis.
davidal66 ... agree with you regarding the interim report. He made it pretty clear on the call: "it was agreed with the FDA that no matter what the results are for the point, this is a single study that they are going to allow or need to put the drug on the market, and they need the safety data".
We'll find out soon enough.
Some interesting insights from the Q4 call:
> "the point that we were recruiting very well in a trial which is a control randomized by open trial, which means that the doctors and the physicians know what they are getting, we are the only blinded party in this trial, is in my mind might be a meaningful thing that at least the patients and the doctors felt that there is a good chance that this will be a great drug, and that’s why they’re recruiting"
He has brought up this point before, and it is interesting that he is consistently delivering this message. He is right: recruiting was successful because doctors and to a degree patients (who do research on their own) were excited about the drug's potential.
> Regarding his comments on checkpoint inhibitors, he talked about combining it with VB-111 since one won't affect the other. Many patients are taking this multi-prong (cocktail) approach since each drug has different mechanism of attacking the cancer cell. Cancer cells mutate. They have need for blood (nutrients), they have different cell surface receptors, they use different pathways .. and more ... so it seems appropriate to use different mechanisms to attack it.
> Regarding dropouts, he was clear that this issue happened early on and it has been addressed; it is not happening anymore. It sounds like it happened on the avastin arm from patients that wanted to be on the VB-111 arm and didn't get selected for it.
> Regarding the interim report, he said, "It’s going to be quite close to the endpoint of the study or to the top line results, and therefore it was agreed with the FDA that no matter what the results are for the point, this is a single study that they are going to allow or need to put the drug on the market, and they need the safety data. .. The only thing that we will have in this interim analysis is the green light to go forward, but because at that point a trial will already be at the position that half of the patients will have at least one year follow-up, if we will get the green light to go on with the trial, then we believe that that will be a great signal."
It sounds like what he's saying is that the FDA will review the data and will give the "green light" to proceed if VB-111 is found safe (which it has been for multiple indications). *fingers crossed* I hope no serious AE gets reported. So far, patients are not reporting any serious AE so that is a good sign. I have seen drugs with worse (much worse) safety profile and they still get approved.
> For ovarian: "most current therapies fail to prolong patient survival ... There was also an overall survival benefit signal with a tell of more than 40% at 3.7 years for the therapeutic dose cohort, despite the fact that most patients in the VB-111 study had tumors that previously had progressed on several lines of therapy, including kinase inhibitors."
Phase 2 had a small population but this speaks to its (huge) potential impact to help ovarian cancer patients. It also is a good indicator for phase 3 since they did not hand-pick patients that would (falsely) give positive results in phase 2. (phase 2 rGBM recruiting was also done this way so there's a better chance that ph3 would have similar outcome)
Overall, I was please with the presentation. However, they did not address why the last funding was needed (was it for facilities? was it for ovarian phase 3?)
So I looked in the 20-F and found some helpful info.
NOTE 9—COMMITMENTS:
> "In October 2016, the Company entered into a long-term lease contract for approximately $2.0 million over 7 years for a new facility in Modiin, Israel with the option to extend for an additional two periods of three years each ... The expected future minimum lease payment is $182 thousand for the year ending December 31, 2017, $312 thousand on an annual basis for the years ending December 31, 2018 through December 31, 2023, and $130 thousand for the year ending December 31, 2024.
... The leases will expire in 2019. The expected lease payments for the years ending December 31, 2017, 2018 and 2019 are approximately $126 thousand, $50 thousand and $17 thousand, respectively."
These amounts are minimal and I agree that they won't significantly impact the company's cash position for operations.
> " In January 2015, the Company entered into an agreement with a Contact Research Organization (“CRO”) according to which it will receive project management, clinical development and other related services from the CRO for the execution of the Phase 3 rGBM clinical trial study in consideration for up to $18.7 million. Through December 31, 2016, expenses in the total amount of $9.2 million were incurred."
This item is pretty significant but I would think it has been factored in during the initial financing. ?
> "As of December 31, 2016, the total royalty amount payable by the Company, before the additional Libor interest, is approximately $19.0 million ($23.3 million including interest)."
Payment to the Gov't of Israel is also significant. This is from grants received. May be a reason why the company received favorable terms for their new facilities.
Risk factors
> "For instance, in order to complete our Phase 3 trial of VB-111 in ovarian cancer, we will need to obtain additional funding."
Really? I thought ovarian phase 3 has been funded but I guess we should expect another funding in the near future.
oren, small margin calls work the way you suggested. But in this case, it is a significant margin call that the account owner didn't meet by the deadline. It is very normal for a broker to sell at the end of the trading day to meet a margin call because the account holder has missed the deadline.
I am just relieved it that the trade is not due to VB-111 or VBLT - or at least it doesn't seem like it after the stock rebounded. Onward to the press conference ...
Since the stock has rebounded today, it looks like yesterday's action was due to a (huge) margin call. Someone needed immediate liquidity. Some lucky folks got shares at a discount as a result.
My take. Whoever sold wanted to cause this type of panic and to trigger a few stop loss orders.
I would not think it's someone with inside info because the trade is too blatant and easily traceable.
It could also be Thai Lee dumping some shares to get liquidity. She was never into biotech and only inherited these shares because of a loan default.
109 events can happen on any arm. Assuming 50/50 split between avastin only and VB-111 arms, I would think a significant number of events would come from avastin only (based on numbers from past trials) before March 2018.
Based on your assumptions, I would think that the longer a company waits after the interim results then the higher the acquisition/partnership price (assuming continued positive results).
For example, Otsuka recently acquired a "phase 3 ready" company (Neurovance) for $250M. The price would have been more than double (much more) if the company presented positive phase 3 interim results.
Agree. It wouldn't surprise me if solid interim numbers lead to a buyout before ph3 is even over. That's why I hope the company doesn't sell. Avastin peak sales is around $6B (I think) so selling to Roche would be an ideal match. I would prefer a partnership over an acquisition in that scenario.
VB-111 may work for other indications so getting sold limits the company's potential to partner with other companies.
I hope they don't/never get acquired. I want to see 1) the pipeline develop; 2) for how many other indications VB-111 gets approved; and 3) if/when VB-111 gets approved for frontline (combo) treatment for GBM.
It is also to maintain/build relationship with the analysts. For example, Roth Cap recently said this about VBL:
Roth Capital analyst Joseph Pantginis notes that VBL Therapeutics has announced positive follow-up overall survival data from the Phase 2 thyroid cancer study with VB-111. The analyst believes VB-111 represents a "strong potential option" for patients with recurrent glioblastoma and looks forward to clinical progress in the Phase 3 rGBM study. Pantginis projects upside from future clinical updates, expansion opportunities for new indications as well as partnership potential for VB-111. He reiterates a Buy rating and $17 price target on the shares.
Presenting at ROTH on 3/14 at 10:30 ET -- doubt anything significant will be presented.
Interesting video .. that someone would take the time to create a summary of VB-111
http://www.dailymotion.com/video/x5ejnvl_vbl-s-thyroid-cancer-drug-clears-phase-2-vblt_news
Even though avastin is not effective for OS, it is the SOC for rGBM. Hopefully, VB-111 shows that it is more effective, and displaces it as the SOC for rGBM. This will pave the way for VB-111 to be considered for other types of cancers, and potential frontline combo treatment for GBM.