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Clay Siegall (SGEN) “If you see a 100pt study that takes a long time to accrue then run away fast. If you see physicians fighting for the drug & accrual is fast..then the drug probably works.”
... if you start a trial, close your eyes, and only ask how fast accrual is going, you probably will find out if your drug works or not.
March 8 - Q4 and Full Year 2017 earnings out. Could be some interesting updates from current ph3.
Remember the ph2 data analyzing LE and CE? I think the ph3 result will attempt to segment the data in this way. Thus, the CE (median = 4 doses) will be the subgroup that shows positive results.
But, does this mean that those that received 1-3 doses and moved on would have done better if they continued to receive at least 4 doses of VB-111? Is there positive correlation between # of doses and mOS?
Reference: http://ir.vblrx.com/news-releases/news-release-details/new-phase-2-patient-data-presented-asco-strengthen-evidence-anti
Yes - still have shares. Similar to wcopeland, I don't get caught up in daily stock movement. Big event is March/April.
The BMY connections are really interesting (and perhaps revealing?). I think AZN, MRK and Roche are also in play. You just never know in the m&a world. MRK just had keytruda approved for another indication in Japan so I wonder how the existing VBL/Nanocarrier relationship will play out in any potential m&a discussion.
AACR Wednesday, February 14
B07 Immunologic activation in recurrent high-grade glioma patients with durable complete response
following treatment with Toca 511 and Toca FC. Clark Chen, University of Minnesota, Minneapolis, MN.
B08 Toca 511 and Toca FC: Durable complete responses observed in patients with IDH1 wild-type
and mutant recurrent high-grade glioma (rHGG). Bob Carter, Massachusetts General Hospital, Boston,
MA
http://www.aacr.org/Documents/CNS_Poster%20Session%20B_website.pdf
oren's identity revealed!
All kidding aside, I read this and your past comments came to mind.
https://www.buzzfeed.com/stephaniemlee/ascendance-biohacking-herpes-gene-therapy?utm_term=.kiG5oq91L2#.xtoZboGM82
“I do what has to be done for the science to move forward, and for other people to feel free enough to be able to seek interventions for themselves,” he told BuzzFeed News last week. He likened himself to Jonas Salk, who developed the first effective polio vaccine, and Louis Pasteur, pioneer of pasteurizing bacteria: “I’m a biohacker in the Salk or Pasteurian sense.”
Where do you think the approved treatments got their start?
In the past, I did hope that VB-111 could be dripped into the tumor area but I don't think they're doing that.
Yes, I think they may have lucked into one of the agents and they hinted at this: "the other has been tested for human use in several unrelated clinical trials".
Yes, they use the word "cured" but also stated that the cancer came back in 3 of the mice.
Still not disclosing the agents involved so it'll be interesting to see what they're using for treatment.
Cancer ‘vaccine’ eliminates tumors in mice
https://med.stanford.edu/news/all-news/2018/01/cancer-vaccine-eliminates-tumors-in-mice.html
The approach worked startlingly well in laboratory mice with transplanted mouse lymphoma tumors in two sites on their bodies. Injecting one tumor site with the two agents caused the regression not just of the treated tumor, but also of the second, untreated tumor. In this way, 87 of 90 mice were cured of the cancer. Although the cancer recurred in three of the mice, the tumors again regressed after a second treatment. The researchers saw similar results in mice bearing breast, colon and melanoma tumors.
The Toca-511- and 5-FC-treated animals showed slower tumor progression than the control group after 6 cycles of 5-FC treatment. On average, progression in the Toca 511 and 5-FC treatment group was blunted over time and stabilized through cycles of 5-FC (Figures 1B and S1B). Treatment with 5-FC resulted in prolonged survival compared to PBS control (p = 0.05) (Figure 1C). Five of 9 tumor-bearing mice (55%) remained tumor free after cessation of 5-FC until the end of the study (day 90). Prolonged survival after cessation of treatment suggested that survival was at least partially due to the induction of anti-tumor immune response. To further evaluate the effect of Toca 511 and 5-FC treatment on the induction of anti-tumor immune responses, CT26 cells were implanted into the right flanks of “cured” mice as well as naive, age-matched mice on day 90 after the original intrasplenic tumor implant. Tumors engrafted and grew in all naive animals; however, tumors were rejected in mice that had previously cleared CT26 liver metastases through treatment with Toca 511 and 5-FC (p = 0.028 versus naive) (Figure 1D). Animals that received Toca 511 and 5-FC did not exhibit signs of toxicity (Table S1).
http://www.sciencedirect.com/science/article/pii/S2372770517300487?via%3Dihub
Promising development - but no CR:: a virus injected directly into the bloodstream can reach tumors deep inside the brain and switch on the body’s own defense system to attack them.
...
He said their trial had shown not only that a virus could be delivered to a tumor deep in the brain, but that when it reached its target, “it stimulated the body’s own immune defenses to attack the cancer”.
...
In all nine patients, there was evidence that the virus had reached its target, they said. There were also signs that the replicating virus had stimulated the immune system, with white blood cells or so-called “killer” T-cells being drawn to the tumor to attack it.
Because the virus only infects cancer cells and leaves healthy cells alone, patients who received the experimental treatment reported only mild side-effects such as slight flu-like symptoms.
https://www.reuters.com/article/us-health-cancer-virus/immune-boosting-virus-could-be-used-to-treat-brain-tumors-idUSKBN1ES1R3
Intravenous delivery of oncolytic reovirus to brain tumor patients immunologically primes for subsequent checkpoint blockade
Intravenous reovirus associates with multiple peripheral white blood cell subsets in patients
On the basis of the murine experiment results, we recruited nine patients to a phase 1b window of opportunity trial (table S1), where each patient was treated with a single, 1-hour intravenous infusion of 1 × 1010 TCID50 (50% tissue culture infectious dose) reovirus ahead of planned surgical resection of his or her brain tumor. Treatment was well tolerated in all cases, and surgery was undertaken 3 to 17 days after reovirus infusion. The most commonly observed adverse events were lymphopenia (grades 1 to 2 in all nine patients, grades 3 to 4 in six patients) and flu-like symptoms. Median overall survival from the day of reovirus infusion to death was 469 days (range, 118 to 1079 days), which is consistent with the expected survival for this group of patients that have variable cancer diagnoses.
http://stm.sciencemag.org/content/10/422/eaam7577.full
Promising development - but no CR:: a virus injected directly into the bloodstream can reach tumors deep inside the brain and switch on the body’s own defense system to attack them.
...
He said their trial had shown not only that a virus could be delivered to a tumor deep in the brain, but that when it reached its target, “it stimulated the body’s own immune defenses to attack the cancer”.
...
In all nine patients, there was evidence that the virus had reached its target, they said. There were also signs that the replicating virus had stimulated the immune system, with white blood cells or so-called “killer” T-cells being drawn to the tumor to attack it.
Because the virus only infects cancer cells and leaves healthy cells alone, patients who received the experimental treatment reported only mild side-effects such as slight flu-like symptoms.
https://www.reuters.com/article/us-health-cancer-virus/immune-boosting-virus-could-be-used-to-treat-brain-tumors-idUSKBN1ES1R3
Intravenous delivery of oncolytic reovirus to brain tumor patients immunologically primes for subsequent checkpoint blockade
Intravenous reovirus associates with multiple peripheral white blood cell subsets in patients
On the basis of the murine experiment results, we recruited nine patients to a phase 1b window of opportunity trial (table S1), where each patient was treated with a single, 1-hour intravenous infusion of 1 × 1010 TCID50 (50% tissue culture infectious dose) reovirus ahead of planned surgical resection of his or her brain tumor. Treatment was well tolerated in all cases, and surgery was undertaken 3 to 17 days after reovirus infusion. The most commonly observed adverse events were lymphopenia (grades 1 to 2 in all nine patients, grades 3 to 4 in six patients) and flu-like symptoms. Median overall survival from the day of reovirus infusion to death was 469 days (range, 118 to 1079 days), which is consistent with the expected survival for this group of patients that have variable cancer diagnoses.
http://stm.sciencemag.org/content/10/422/eaam7577.full
Toca 5 Trial link: https://clinicaltrials.gov/ct2/show/NCT02414165
I like this trial. Avastin is on the Active Comparator arm, and not in the Experimental arm (won't taint the outcome).
However, Toca 511 and 5-FC treatment significantly
reduced the Mo-MDSC population.
Treatment with 5-FU has been shown to induce
selective apoptosis of MDSCs, thereby
decreasing the burden of these cells in the
murine spleen and tumor environment,
but without depleting host T cells, natural
killer (NK) cells, dendritic cells, or B cells, and
promoted T cell-dependent anti-tumor responses.20
Therefore, the elimination of MDSCs
represents a promising approach in cancer therapy.
Future studies are needed to determine
suppressive activities of different subsets of MDSCs that could
improve the development of novel interventions for cancer treatment
in colorectal metastases.
In conclusion, our data from disease-relevant in vivo tumor models
suggest that Toca 511 and 5-FC is safe, efficacious, and represents a
novel tumoricidal and immunotherapeutic approach for the treatment
of liver and brain metastases for patients with mCRC. Importantly,
this work demonstrates that Toca 511 in conjunction with
5-FC promotes both direct killing of tumor cells by local production
of 5-FU and induction of a local and systemic immunotherapeutic
response, resulting in long-term survival by selectively depleting a
highly immunosuppressive population of cells, MDSCs. We believe
that this platform may provide improved treatment outcomes for
individuals with mCRC when translated into clinical trials
(NCT02576665).
http://www.cell.com/molecular-therapy-family/oncolytics/pdf/S2372-7705(17)30048-7.pdf
I haven't seen one way or another whether fever was present in the 5 CRs.
Let me know if you find anything.
Agree. I think fever is an indication that the immune system has been activate and recruited to fight the cancer. With Toca 511/FC I find it interesting that the company's goal is to create products "designed to activate a patient’s immune system against their own cancer from within."
Also in their earlier studies they found that previously treated mice retained their abilities to fight cancer. This is a sign that the treatment could train the immune system to continue to fight current and future cancerous cells:
"Cellular immunity was evaluated in splenocyte populations
obtained from these previously cured mice by measuring
the number of IFN-? producing cells with ELISPOT
assay. Target cell–stimulated IFN-? responses of splenocytes
derived from cured mice were significantly higher
than splenocytes obtained from naïve control mice (P =
.0005; Fig. 5A). Furthermore, mixed lymphocyte–target
cell reactions using splenocytes from previously cured
animals, monitored by xCELLigence electrical impedance
analysis, showed progressive killing of Tu-2449 target cells
over time in an effector:target ratio–dependent manner,
compared with splenocytes from naïve mice (Fig. 5B, C),
and were similar to those obtained after stimulating splenocytes
from naïve animals with INF-? treated Tu-2449 cells
(Supplementary Fig. S6). Taken together, these results indicate
that RRV-mediated prodrug-activator gene therapy
stimulated endogenous antitumor responses that could be
reactivated >300 days later."
https://tocagen.com/wp-content/uploads/Hiraoka_et_al_Anticancer_Immunity_Neuro-Oncol_2017.pdf
3 more months until topline results. Other news will not significantly move the stock.
Thanks for the link. I read the article and my take on it is:
1) Decision (to approve/not approve) will be made at the beginning of 2018. The 3rd phase of the trial will be completed around this time.
2) The "special track approval" that he talked about was for orphan status/fast track.
He's confirming stuff that has already been made public. How do I know this? If what you said is true then the stock would be in the 40s by now. News travel fast no matter the language it's in.
Did the guy really ask about his "wet dream"?
THANK YOU, wcopeland, for bringing some clarity/sanity to this topic. I completely agree. IIRC when VBL mentioned the 15 months, it was along the lines of "53% of the patients were alive at 15 months". 53% = 9 out of 17. As long as the 9 are alive, the mOS would be unknown (but increasing).
I would also caution anybody from reading too much into a word or phrase. Ongoing means ongoing - it's vague so it can mean anything. Unless the company specifically states, "We have X events" I would not jump to the conclusion that ongoing means X events have or have not happened. It is all just speculation, which may be fun to do but dangerous when you're basing your investment decision on it (false assumptions).
As wcopeland said, some things may be lost when Dror is using his 2nd language.
I would guess there has been partnership and acquisition discussions with US BP. It happens a lot but usually it's at a steep discount. VBL wants a premium.
The offering provides VBL with sufficient funds to stand on its own for a while, which provides some leverage if future acq discussions were to happen.
jumpinjackas, NanoCarrier has rights for all indications. So if rGBM, prOC, and thyroid (and future indications) all fail then the investment would be somewhat worthless for VB-111.
But based on ph2 results for the 3 indications, I would think that the $15 mil investment has a good chance of returning value back to the company.
Agree wcopeland. That's my read as well. For longs that think the price will be much higher, it should not matter if the current price is $6 or $9. If phase 3 rGBM is approved the current price is insignificant.
The offering does show that the company/Dror is blinded to the results. If they knew the results or the number of events for each arm (as some have suggested) then it would not make sense to do an offering now. Passing rGBM phase 3 would significantly increase the stock price and they could raise a lot more money at that time.
What this shows is that management truly does not know but they want to make sure that they have enough funds (whether ph3 rGBM passes or not) to carry out prOC ph3.
It is actually a solid management decision if you play out the different scenarios.
Great videos. Well done on the testimonials:
https://www.facebook.com/Tocagen/videos/1038303152858779/
https://www.facebook.com/Tocagen/videos/1265351910153901/
https://www.facebook.com/Tocagen/videos/1577412432281179/
nm
BIOMARKER ANALYSIS SUPPORTS THE VB-111 DUAL MECHANISM OF ACTION
supporting info:
https://academic.oup.com/neuro-oncology/article-abstract/19/suppl_6/vi26/4590394?redirectedFrom=fulltext
Per SEC filing, this is part of the $100 mil shelf. This offering is similar to the June 2016 offering, imo.
Stifel summary
Toca 5 phase 3: > 50% enrolled
Interest in adding Toca 511/FC to frontline SOC
Interim results: at 50% events, 2H18
Check out the presentation:
http://ir.tocagen.com/phoenix.zhtml?c=254300&p=irol-calendar
Looking back at Dror's comments in the last earnings call:
"And actually as you all know, it’s quite difficult to do deals on certain indication and then split it and get someone else to actually sell the drug for another indication. It’s very difficult in the U.S. It’s difficult in most places around the globe. So we are looking for relatively small or very [exclusive] territories where we are going to license the drug for the different indication. Of course, in the deal one can put economy that will actually give us benefits from the different indications, and that’s what we are working on. But the whole idea is that this type of deals shouldn’t harm it any way the global potential deal that we can have.
And again, it can be something that we’ll split geographically between us and strategic partner with the successful results in 2018. But this geographic deal that we’re talking about actually not going to jeopardize any of this big global deals. But it’s going to include all indications. And actually, we are even planning, if it will go forward, to take advantage of one of the territories, which has a significant number of patients with lung cancer. And then of course that could be a good place to do some of the trials as part of global trials."
Dror was pretty much telling us about the deal without telling us about the deal. Sounds like Japan is one of the places that will participate in the "exploratory clinical study of VB-111 in combination with checkpoint inhibitor in lung cancer in Q1 2018."
"VB-111 is expected to receive early approval." That's interesting since Dror has said in the past that this won't happen because 1) it's under a SPA and 2) we're so close to the topline data.
Thoughts on whether this is a sustained move or a head fake?
Agree. The company has resources and experts that can analyze the data and make a very educated recommendation. They may not be right but for a mid-size company, $15 mil is a lot of money. I would think that they made every effort to make sure they had high probability of profiting from this decision.
It is a significant deal but NanoCarrier is not a large company ($280 mil mkt cap). If it was the same deal but with a bigger player (Takeda) then I believe the stock action would be more significant.
The median survival in this trial is nearly double compared to historical data, according to Dr. Chen. In the subgroup, median survival was 14.4 months compared to approximately 8 months for historical controls. In contrast to the ongoing, durable responses observed in this study, patients treated with the chemotherapy lomustine (Gleostine) had an overall response rate of about 4.3%, which, like bevacizumab (Avastin), was not durable and typically lasted a few months.
A limitation of the study is that it was a single-arm trial without a control group.
http://www.ascopost.com/News/58198
Q3 2017 Earnings Release Wednesday, November 8, 2017
http://ir.tocagen.com/phoenix.zhtml?c=254300&p=irol-calendar
Durable responses observed in recurrent high-grade glioma (rHGG) with Toca 511 and Toca FC treatment
http://www.abstractsonline.com/pp8/#!/4557/presentation/619
More than a quarter of patients with a common type of deadly brain tumor were alive 3 years after undergoing new gene therapy, promising clinical trial reveals
http://www.dailymail.co.uk/health/article-5036149/25-high-grade-glioma-patients-live-3-years-trail.html
Investigators said once inside the cancer cell, the virus delivered a gene for an enzyme, cytosine deaminase (CD). As the virus began to replicate and spread to other cancer cells, it programmed them to make CD and once inside the cancer cell, CD converted Toca FC into the anticancer drug 5-fluorouracil, which killed the cancer cell.
Trial offers optimism in treating recurrent brain cancer
https://lifesciencedaily.com/stories/23365-trial-offers-optimism-treating-recurrent-brain-cancer/