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Maybe Rene. Bright Star in a Dark Sky!
It would make the radar screen for every CNBC type broadcast.
I shouldn't have said small cap is sometimes safe haven though... because that is probably not true. What I was thinking of was that biotech, though risky, is sometimes spoken about as a safe haven when the broader markets take a big slide / or at least when the economy tanks. The idea being that everyone needs their medicine... while getting the next iPhone can wait.
The market is upset with China Mfg Data:
Or new orders for China Mfg or something. Supposedly also due to weakness in emerging market currencies.
Sometimes micro-mid caps like this don't drop with the broader market, but I think that today that was the main cause.
Not to be picky, but I believe gazillion has 2 l's.
Thank you Flipper, for the document on the review committee procedures. Valuable stuff.
I do believe that you know what you are talking about when you talk of the possibility of an early approval... I just had to come to grips with the fact that half of a gazillion dollars is actually a great deal of money, and zero dollars is a very small amount of money. Sort of a log scale for the potential effect on my life.
I'm not a Doctor, but thanks for the complement.
My Wagering Position for What it is Worth:
I was all in... alllllll in. I finally got scared and pulled back. Pulled too far back and lost some ground coming back in.
Novice antics. When you have too much in you become too emotional. I knew that, but did it anyway. When you have to much on the sidelines you become anxious and can buy in high.
In the end I find the correct balance between greed and fear is one testical (or ovary) not two. This is a one testical situation. Not a half, and not two. At least for me.
When I hear people talking about digging money out of their couches to invest further, I worry about them, a little.
Everything I know about Northwest says that not being invested now would be a big mistake. But I don't know everything. Many if not most on this site know much more than me, but they too realize they don't know everything.
Linda Powers bought 6,468,153 shares on 12/12/2012. Certainly everything she knew said it was a good investment at that point in time. That was about a year ago, but there was still more data available to her then than we have now... no? The only thing more that we have is the date when 66 events was reached.
Dr. Linda Liau, M.D., Ph.D, was heavily involved in the development of DCVax-L for GBM, and I believe she was chief of the early trials, and possibly the current phase III trial. She is a very actively practicing neurosurgeon with a Ph.D. in Molecular Neuroscience. She lost her mother to GBM when she was a resident. A life experience like that motivates people in big ways. All those Oscar winners pointing at the sky are for real. Well, I guess I don't know that, but Dr. Linda Liau is for real. I know that.
http://www.cancer.ucla.edu/Index.aspx?page=644&recordid=304
Like many people I changed my life course as the result of a personal loss. For me that might have been a mistake because I switched from a field where I was very strong to one where I was weak. But for Dr. Linda Lau it was only a matter of final specialization. I've only known one M.D., Ph.D.. Dr. Larry Miller at Resonex MRI. He was a phenomenon. Head of the Advanced Projects group (him and a talented tech), he made an enormous number of large contributions to the development of that MRI system. And I don't think either of his parents died for need of an MRI.
NWBO has an outstanding, albeit small crew. They had a much larger crew until finances forced them to trim down. By that time DCVax-L was already developed, and it did not make sense to keep a large crew for the extended journeys ahead of them.
But here they are, at the end of that journey. A few things to grapple with for us, but not the quality and sincerity of NWBO's effort thus far. Not Dr. Lau's efforts. Not Linda Power's efforts.
So what to worry about. One concern often stated... and recently brought back up in that Apology to Adam Anti blog. IMUC failed so why not DCVax-L. The difference is the number of antigens. Is that a big difference? This is not my field. But it's a numbers game, right? It's a microbial war and the numbers must matter. It's a statistical thing. These T-Cells sniff around looking for antigens reported by the Dendritic Cells, and sometimes get fooled by suppressor's. The more antigens, the greater the chance that an antigen is exposed distant from an inhibitor. The PD-L1 inhibitors, for example, are not floating around in the interstitial space. They stick out the side of the cell membrane like the antigens do. And they can't stick out everywhere. More varied antigen targets may not improve the odds for a given programmed T-Cell, but it improves the odds of a security breach for the tumor cell, for some T-Cell targeting the right antigen.
So, I argue that even I can come up with reasonable explanations for why DCVax-L could be far more effective than ICT-107 (IMUC's currently/apparently failed immunotherapy... at least for now). That doesn't mean DCVax-L is better than ICT-107; it just means that the bashers that argue that ICT-107's failure strongly implies DCVax-L's failure are not trying very hard to see any other possibilities.
The other main concern appears to be that there might be a lot of people in this for the run-up to interim review results, and others in it for the early approval possibility, so that the likely recommendation of continue will actually tank the stock.
One nut now. And if that were to come about, I will be putting my other nut on the line because a simple continue is probably all that is needed for a number of other developments to fall into place. It does not benefit me to say this. But hearing the concerns recently posted, I thought I should share these thoughts.
Aside: (So as not to be touting PD-L1 inhibitors, one of the few clinical summaries that I read about such made it sound like surrounding healthy tissue may actually point at the tumors by increasing the amount of PD-L1 they present. Perhaps the surrounding cells feel the heat generated by the excess tumor metabolism, or sense the excess acidity generated... who knows, but it appears that the contrast in PD-L1 expression between the tumor and the surrounding tissue helps clue the immune system as to what is tumor and what is not. So it is unclear that simply wiping out all PD-L1 function would always improve the situation... and further, as Flipper pointed out, there might be side effects... For example; PD-L1 apparently helps healthy tissue protect itself from inflammation after tissue damage. The cleaning crew comes in to eat the spill and kill any pathogens feasting on the spill, and the surrounding healthy tissue raises the PD-L1 flag to distinguish themselves from the carnage. Not to say it shouldn't help... it apparently does often, but it is not a panacea and not without issues.)
Pardon my animorphodizing the individual cells etc, gpb.
Uncomfortable Things:
1) Yahoo charts on NWBO have erased the peak during the last PR blitz, and it has been that way for some time now. Very strange.
2) Linda made no mention of the pending application for German clinical funding during her talk in SF. Not the matching funds, but the application by the hospitals to get the entire clinicals funded.
3) During that talk in SF, Linda appeared to not only be petitioning for a partner for prostate, but for a buyer period. Given that any such effort would be far more likely to succeed after the interim review, why this effort now? All of our estimates on the odds for various outcomes from that review end with the unknowns on enrollment specifics. NWBO has no unknowns in that regard.
There was a lawsuit when Provenge was delayed.
I think the deal was that the review board recommended an early approval, with a pretty clear vote, and the FDA decided no. Protests and a lawsuit followed. One of the points in the lawsuit was that one of the people in the FDA that voted against the early approval was associated with a direct competitor.
Not sure it makes sense to anticipate a problem Flipper. But if something similar were to come about, it would make sense to contact the same legal firm that handled that lawsuit and also the major players that initiated the lawsuit. Since there were also protests against the FDA, we could track down the major players there. Probably best to locate the ones that don't have a bunch of stock in Dendrion.
But I just did a quick read on that last week. Could be remembering things wrong... and I don't know what the outcome of the trial was, nor whether there really was anything improper by the FDA. I do know that the path is paved for such action.
Hate to bring up Provenge because some consider it a failure. (It is an immunotherapy similar to DCVax-L for prostate). However, the failure is due to the high production cost. NWBO focused on production costs and is able to mfg DCVax at about 1/3 the cost of Provenge. That is a huge!!!!! difference!!!!!
So NWBO will likely grow into a large and successful company on it's own right if it gets through these trials. For that reason it might not make sense to sell all your shares if and when approval comes.
Further: By having parallel clinicals in Europe, NWBO gives a second path for approval. But it also creates a situation where the FDA would look very suspect if the results were good and approval was denied... because if Europe approves the therapy and the number of patients skyrockets, and the results are good and widely known, which they would be... then the world would turn and look the FDA in the eye and ask what is going on?
Market Cap 3rd Try (Last was backwards):
I woke up realizing I had written that last post using diluted when I meant undiluted. So here is the fix now that I have confused anyone who tried to make sense out of it.
I have noticed that the market cap numbers listed are always simply calculated as the pps x the nominal, ie undiluted shares outstanding. If someone wanted to project the expected rise in NWBO pps in response to DCVax approval based on the change in market cap observed for a similar drug approval for another company, then they would best divide the expected (undiluted) market cap change by the undiluted number of shares.
As for my guess on how high NWBO might rise if it got an early approval and no news yet on Direct...
I would average all the guesses I have read over the last couple of months. Those guesses range from $30 to $50/sh.
I don't know what number to use for projected market cap. I have heard the $3B number a lot, but I have also heard lower numbers. $3B would correspond to about $77/sh. Not sure I believe that. Maybe with good news on Direct rolled in there, and a short squeeze. With further news on exciting Direct performance, maybe higher than $77. People don't trust early clinical data all that much, but if you have patients on the news thanking NWBO in big numbers for curing their inoperable cancer... I think $3B market cap could even be a little low.
"Market Cap" again.
Let me try that again. My edit time expired.
There are diluted shares outstanding... and there is also diluted market cap. The cap you see published on Yahoo finance etc, is diluted market cap, calculated as pps x diluted shares outstanding. They just don't label it as diluted. Strange.
So...
If you were projecting the pps of NWBO after approval of DCVax-L by comparing it to another company's situation after a similar drug approval:
and the comparison was based on an acquisition price, then I would agree gpb, that Flipper has been breathing the helium too long. Because in that case, you would want to divide that acquisition price by the true number of shares outstanding to get the actual value of the stock.
However, as I recall, Flipper was projecting based on the "Market Cap" change that was seen for another company upon similar drug approval. In that case, the market cap change he was referring to would likely be the published (diluted) market cap, and so the expected pps change for NWBO in the same circumstance would be calculated by dividing that diluted market cap change by the diluted number of NWBO outstanding shares. Assuming the two companies had similar levels of dilution (dilution as in outstanding warrants).
True?
"Market Cap"
If you are estimating the market for DCVax and calculating the expected final market cap as a function of projected annual sales, etc... then you are right gpb.
But as I recall, Flipper was comparing NWBO and DCVax to another company, and it's product, and was gauging the possible future NWBO market cap on that other company's market cap. In that case, if the other company's market cap was without dilution... ie something off a vanilla website such as Yahoo Finance, then that scaling should be using the same undiluted (inaccurate) market cap for the NWBO projection. That is, if you assume the same level of understatement for the two market caps.
Apples to apples... and dust to dust... or something like that.
Since on 12/31 likely tax motivated?
As opposed to any change in sentiment.
I'm O.K. if no big news at conferences:
Great to hear that they are presenting at another conference this month. However... personally, I am not counting on any big news and will not be bothered if there is no big news.
I could swear that when questioned at the recent Oppenheimer conference, the CEO estimated max 1 or 2 Direct patient statuses this (entire) quarter, not month.
Sometimes companies go to annual conferences just to stay on the radar. I don't know how big either of these conferences are, but Genentech and many other big Pharma companies are located in the bay area, including south San Francisco. The San Francisco conference is probably a big conference.
I hope there is big news... but it won't bother me a bit if there is not. Big news is imminent, for sure, but whether it is that imminent is hard to say. We are watching the pot, waiting for it to boil.
On the other hand, it is a little strange that they would just now announce the San Francisco conference presentation only a week away. I think a week is too long to be holding news on the interim review; others may know for sure. So... if it is good news, it would most likely be on Direct. But as I said... the CEO did not want us counting on such in the immediate future.
Big Pharma Smoke Screen/Diversion:
The recent PR's about big Pharma Immunotherapies appear to be a diversion and preparation for any good news about DCVax-L and Direct and possibly other related approaches from other smaller companies that are well along.
Unfortunately, the idea of injecting the tumor before removing it does make some sense to me. That is, if they wait for many DC's to migrate out of the tumor on the way to the lymph nodes prior to removal.
Maybe.
The other PR barrage from big pharma has been about PD-L1 inhibitors. Those too sounded like a panacea when I first heard about them. But when I looked up actual clinical results off the web, I gained another impression. So... It is very easy to tout a new untested therapy. It is another to fully develop it and prove it out.
Further, if DCVax-Direct works well, then they may have leap-frogged this other process of injecting the tumor before removal. And as a half-way approach between Direct and L, I don't know that NWBIO would not have the rights to use a similar procedure if L and Direct were both approved. They may have such plans for cases where the tumor can and should be removed.
I think big Pharma is scared. I just hope they don't get underhanded.
Thanks Flipper for the patent text: + Catalysts
Reading that patent makes Direct a little more real to me. Many Direct bashers out there on Yahoo. Many Secret Sauce bashers too. Need such positive input to balance that out. Of course results would be better... but again, I hope they are not in a hurry.
In recently listing catalysts that might be gated on the interim findings I forgot to list partnering for L-Prostate. So the list becomes:
1) German Hospitals granted L cost reimbursement by their fed.
2) European compassionate care status for L allowed (I don't remember the details or even which countries... but it is pending.
3) New mfg facility.
4) Partnering for L Prostate.
Any or all of these could be waiting for the interim review. And for most of these, they may feel they need to know that neither fantastic or bad news comes out of that review board. Why spend the time on a difficult debate when it might get real easy one way or the other in a month?
As for the safety net, I forgot about something. As far as the very unlikely but very scary possibility of stopping the L trial due to bad results: They do have somewhat of a safety net in place. They have all those sub-groups that they defined when they setup the trial. I would think that the interim review board would have to look at all of those subgroups. They could make a decision to stop one sub-group while stopping the placebo and allowing early, conditional approval for another sub-group. So the chances of a devastating recommendation, which would already be very small, go way down, and the chances of an early conditional approval of some kind go up. Conditional is not the right word. But the status where they allow you to sell the product but continue reviewing patient data with the right to revoke the approval in the future.
That is if the subgroups are considered individually in the interim review.
Where is the new mfg plant going to be?
Long: I think you corrected me on that prediction of mine once before. Sorry I forgot about German mfg for L already setup. But I don't remember where you guessed the next plant would sprout up.
Gpb: Thanks for the reminder about how inherently risky any biotech is. Once you start breathing helium, you just want more! At least for me and many people.
But... if anything significant gets reported for Direct... then the $1 possibility goes away for the foreseeable future... I hope.
There is that conference on Jan 27. It would be great if something positive about direct was reported. The way the conference was billed gives them two options. They could report early results, or if they don't have anything to report yet, or choose not to report results for strategic reasons, they could talk about optimizing a trial design.
If by Jan 27 they have some positive news on Direct, but plan to wait to get more statistical significance, or wait for better timing for financing, but then get blind-sided by early and unexpected interim results on L, they could change their mind and report on Direct during that conference.
They are all in and they need a net too. But you are right that the net does not exist yet... unless they have it hidden.
And thanks for reminding me that Direct Phase II is only for colorectal cancer, but... could change or if approved early could mean other uses since the inoperable applications are so desperate.
Could you imagine being able to inject into GBM or other brain tumors and not have to do full surgery? It would be incredible. The tumor would be food for the immune system local response. No surgery or car keys required. Just dreaming, but that is the image that keeps coming into my mind. Immune system cells devouring the brain tumors.
Other Catalysts to Follow Interim Review:
There are other catalysts possibly coming soon beyond results for Direct and the interim review, but they may be gated by that interim review.
There is also the application for the European compassionate care status that they have been working on for some time. A response is due. I don't remember where in Europe that status was to apply, but even if it was just one country it would be a big deal, as far as I know. Further, the hospitals being setup for the L trials in Germany applied for reimbursement for the clinical costs. If granted, the $5M/50% funding already offered by the Germans for their clinicals doubles, as far as I know. My guess is that those two decisions will not be made untill the interim review is completed, but will be made soon thereafter. I believe that if either of those decisions go NWBIO's way, it/they will be significant catalysts.
Further, they are apparently going to open another mfg facility somewhere soon. Most think it will be in Europe somewhere. To me, Germany would make a lot of sense. That would also be significant news.
But I'm not counting on results for Direct any time soon. In the recent Oppenheimer conference, the CEO said maybe 1 or 2 case statuses in Q1. That's through March. She said they are having to spend more time in phase 1, where dosing and intervals are played with for best results and least side effects.
What I gather from the blogs is that Direct is an order of magnitude more valuable than L. Hard to imagine, because L is so valuable. But at the same time, if it is that valuable, I don't care if they take an extra quarter to get it to phase 2. In fact, I hope that financing and other pressures allow them the luxury of fine tuning the dosing, interval, and anything else they are allowed to alter such as modifications to whatever the chemistries are that accompany the dendritic cells, as well as details of the dendritic cell prep. Anything they can tweak they should be tweaking until they are absolutely satisfied that they have optimized it. That is what I would want them to do, and I am heavily invested.
In front of Direct is a huge amount of wood to chop, and I think it is wise of them to spend whatever time is needed to sharpen their axe. We know that the FDA can and does sometimes approve on phase II results, and if Direct works anywhere near as well as hoped, then it would definitely be one of those candidates, at least for inoperable tumors. They also have the option of doing a Phase II in Japan where the likelihood of approval on phase II is even higher.
Further, they do need more funding to finish L. You can only raise excitement with old news so many times. I am sure they would much prefer real news. Big, real news is hard to come by, and they can't afford to waste it. They stand to benefit far more from big news on Direct much later this year when they need funding.
Thus spending more time in phase 1 perfecting Direct is a two-fer. I have a hard time passing up two-fer's and the management at NWBIO probably can't afford to pass up a two-fer.
I think your market cap estimates are reasonable, but I always use the true number of shares including warrants, etc., which was 61M recently. My understanding is that 61M is still a very small number of shares for a company with such a pipeline... rather, the implied market cap of $256M for the current share price of $4.19 is still very small given the upside and likelihood of success.
OU: I haven't sold any stock after learning about the issue.
But it is something I will try to learn more about.
On a practical level, they had to deal with this way back in early development of DCVax-L, whether or not the mechanisms were fully understood. And it doesn't sound like it is a black and white issue. It sounds like some PD-L1 can be overpowered, but too much may be an issue. As you (?) said, or as implied by what you said, timing and dosing effect the PD-L1 expression. And they apparently worked out that timing and dosing.
And King's College and the German institutions probably know a great deal about PD-L1. Not a good time to sell, and plenty of time to learn more about these issues.
OU: I will defer to Flipper.
But I searched GBM and PD-L1. What I found were articles stating that PD-L1 expression in the brain tissue surrounding the tumor actually helps the immune system attack the tumor. This possibly because high PD-L1 in surrounding tissue was often associated with low PD-L1 in the tumor.
http://www.ncbi.nlm.nih.gov/pubmed/23986257
http://www.nature.com/nrneurol/journal/v9/n11/full/nrneurol.2013.197.html
OU: I started down the path of looking for non-native immunosuppressive factors that DCVax-L could likely counter, that ICT-107 would not have been able to counter. Then I ran into this native immunosuppressive factor. Reflexively drilling down on that new information was difficult, because I too am not knowledgeable in this area.
As an investor it may not be smart for me to blindly and openly sort through these types of issues, but I don't have enough background to sort through them myself. I tried. This is a very nasty area. But it is possible to learn this stuff. This blog, as well as the yahoo blog, has members that know a great deal about the immune system, and are often willing to help.
Your views on this native defense for the tumors sounds very reasonable. In the end, we don't need to know why a given therapy works. I agree with that totally, and I think it is a very important truth. But remaining is the question of the patient types (ages, etc.) in the phase 1 trials. If not taken into account... . That is the concern that I see voiced by positive, and hopeful but concerned bloggers.
Maybe only a fraction of patients are PD-L1 Positive.
On the animation that you pointed me toward, it was stated that almost all cancers have PD-L1 expression (if that is the right word). On another, more recent write-up on recent clinical results for PD-L1 blockers, they state that half of the patients were PD-L1 negative and that the PD-L1 blocking therapies did not work very well on that large subset.
So PD-L1 blockers are not a panacea. If DCVax-L passes, as I expect, but is also not a panacea, as it probably isn't, then maybe the combination of the two will prove to be so. It could be that only a fraction of DCVax-L patients would need the PD-L1 blockers, and that fraction could be detected before therapy starts.
Someone on this or our sister blog has repeatedly talked about a likely complementary therapy / drug for DCVax-L. Maybe these PD-L1 blockers were what he/she was talking about.
Thanks gpb.
I like the possibility that PD-L1 might be useful for something like protection of a developing fetus. That would makes sense, but given the back-door vulnerability it creates, you would think it would be rare to show in men. Maybe it is rare in men. Or... of course that was just an example of the kind of mechanism that might explain it.
I am glad that bigger Pharma is still searching for the silver (plated) bullet. While DCVax-L may show fantastic results in progression free survival, with much improved patient well being, and sometimes results in an apparent cure... one could see it more often resulting in an apparent cure when combined with some of these other weapons being developed, such as PD-L1 blocking. I wonder whether the prospect of success by immunotherapies such as DCVax-L has accelerated that search for the silver (plated) bullet. (By plated I mean cheap to produce.)
If and when DCVax-L or Direct bring in big $ for the company, one would hope and expect that NWBIO (= NWBO - $ emphasis) would ramp up research on their findings in the silver (plated) bullet realm. Most of what they know is probably already in Direct, so that with approval of Direct, anything learned there might gain easy approval for use along with their L methodology, if L is still needed. And those silver (plated) bullets might come without royalty overhead.
I don't really anthropomorphize very much. But it is useful for discussion, and when something doesn't fit in those terms I think it makes sense to take a look at it. Having hairs hanging off of malignant tumors that say "leave me alone", and the body sometimes obeys, is a pretty fkd up situation begging further investigation.
Thanks for the Animation Flipper.
That does help. PD-L1 is apparently a white flag that the tumor displays on the surface in response to detecting anti-tumor activity. A white flag as in ... "I'm a good guy, don't kill me", not "I give up". Those tumors are not very honorable.
Knowing that much will give me traction as I read more detailed descriptions of that part of the immune system. Without that, it was all gobbeldy-goop (sp?).
Now I need to learn why in the world such a function would exist. If there is some good function for PD-L1 in the immune system, then PD-L1 blocking with synthetic antibodies would be dicey.
I will keep in mind: This is a quickly expanding field, and any therapy undergoing the lengthy Phase 1,2, and 3 trials required could be improved by the time you get to the end. You can't worry about that. Just know that however good the results, it is likely the process can be tweaked after approval to get even better results. The most worthy of therapies for such a long approval process would be therapies with a broad approach, such as DCVax-L where only minor tweaking or supplementation need be considered after approval.
Liked your crossover analysis Flipper. Especially the conclusion.
My last post was on the wrong blog and was a repeat:
My last post was sort of a repeat of an earlier post. Sorry if you spent the time to read both. It is a little more concise, however. I thought I was on another blog. Darn!
Is PD-L1 a natural immune component?
Some or all cancerous tumors produce chemistries that block/suppress the immune system. There is a lot of work being done in developing antibodies to block the blocking chemistries.
If the blocking chemistries are unnatural, then DCVax-L (and the subsequent avalanche of immune response) probably generates antibodies against these blocking chemistries already.
If the blocking chemistries are natural, however, this would be something that DCVax-L can't deal with. In that case, however well DCVax-L works, (and it appears to work very well) it might work even better if some of these antibodies were added.
How could the blocking chemistries be natural? They could be components that exist in small concentrations in the normal immune system. Such a feedback system could have suppression components as part of negative feedback. If the tumor generates these components in large quantities, then it could overwhelm and imbalance the immune system, forcing suppression.
Most likely these blocking chemistries are un-natural, and thus the immune system can fight them. However, likely they normally hide inside the tumor. If so DCVax-L process would expose them and allow a strong immune response against them. This would be true for many such blocking chemistries, discovered or undiscovered.
This is something that a limited antigen approach like IMUC's ICT-107 can not do. Thus to compare ICT-107 to DCVax-L would be dishonest/evil/libelous.
That is... if these blocking components are not natural. Not to say this is the only advantage that DCVax-L would have on ICT-107, but it would be a very large advantage and somewhat distinct from the advantages normally discussed.
DCVax-L Patient Videos:
http://www.gbmvaccine.com/videos.html
This may be old hat; maybe this has been on the NWBIO website. I don't know. I just saw it on our sister blog. New to me and very very nice. There are multiple videos as you scroll down.
Sorry for the flurry of posts today, but somebody put a huge bag of candy at the bottom of my stocking. I quickly dropped it on my neighbors' doorstep, but a day later, they still hadn't bitten, and I got hungry.
Hope that NWBIO is working on a vaccine for diabetes.
Crossover is Voluntary:
I missed that crossover is voluntary. Thus there could be a group of patients in the control group that stay in the control group upon progression. Seems unlikely that many patients would opt to not crossover, but maybe a few. And maybe a few that die before tumor progression is observed. Thus there could be a small control group population from which to evaluate OS.
But such a small group would have huge variance. Hard to imagine that would be much of a consideration. But I did verify that the secondary is OS (I wanted to be sure). So... if the small non-crossover group does well, it will not be statistically significant, while the same is true in the more likely scenario.
Perhaps for OS stats they should compare the DCVax-L group to the broader statistical base for standard of care in recent history, weighting each patient by whatever typing has been developed for these purposes.
Ou: Glad you asked for the research.
Whether you were joking or not, it was something I wanted to research but was too lazy to do so... particularly with all the bio knowledge floating around this blog.
But I am glad I did. It is a huge decision how much to invest in a biotech company such as NWBO, and a very difficult decision regarding how much to hold through the end of the trials.
A key issue at this moment is the difference between IMUC's ICT-107 and NWBO's DCVax-L. Here on this blog, we all know that using tumor lysate allows DC exposure to all the available tumor markers, vs a handful for many approaches such as ICT-107. What I didn't know is whether those markers include the anti-immune-system agents generated by the tumors. After briefly researching it, I think that it does include such factors.
Brystol-Myer bought antibodies in development to counter some of these anti-immune-system agents. The expected annual market is $2B for one of them. DCVax-L likely generates these same antibodies, and likely with memory. Further, it likely generates scores or hundreds of such antibodies that counter the tumor defenses. Again, this is something ICT-107 could not do.
Unless some of these factors are natural. DCVax-L does not work on naturally occurring anything, as the immune system does not work on naturally occurring anything. Some of these factors might be normal parts of the immune system balance, but produced in large quantity by the tumors, with no negative feedback, generating an imbalance in the immune system. DCVax-L cannot fix that. However, any attempt to fix that would have side effects, so any such factors are not the best candidates to tamper with anyway.
In summary, I feel even better about DCVax-L after doing that research. Flipper and OU and John and others contribute a great deal to this website which helps me to evaluate risk. That is very valuable, so even though you were joking... it is not unreasonable to ask for something in return.
I like the odds at this point. Even Flipper's recent calculation of risk that bothered OU was roughly 90% pass.
1st two Anti-Immune Agents researched are proteins.
Pancreatic cancer generates PD-L1 and B7-H1 anti-immunity agents. Both are proteins. That is a good sign.
Most (though not all) proteins have enough polar groups to be soluble in water. Thus the tumor generated anti-immunity agents referenced in recent articles about GBM, and described only as "soluble" may well be proteins.
Next is to find reports specifically describing the anti-immunity agents generated by GBM tumors. But it looks good on that front for DCVax-L and bad for ICT-107.
However, if these agents are proteins then why does the immune system not detect them already and attack them? Maybe the agents remain buried in the tumor. If so the DCVax-L process would be ideal for generating a response to these anti-immunity agents as well as any un-natural / mutated tumor proteins (the main desired response).
Again, DCVax-L would likely work on any such known agents, and any unknown agents, which probably outnumber the known agents. That is the beauty of it.
OU: I read your post about progression after writing my last post.
OU research on anti-dc tumor chemistries: Question on crossover.
Will do OU. If the anti-dc tumor chemistries are proteins then that bodes very well for DCVax-L and foreshadows problems for ict-107 (if you can foreshadow after the fact). If these agents are proteins then DCVax-L likely generates an immunity to them, hopefully as in memory. That is the best possible scenario.
I don't expect to understand the entire statistical analysis that Flipper and OU are debating, but I would like to get one step closer by learning how the trial handles the crossover group.
My understanding is: NWBIO wanted to run the study without a control group. That is good. If they believe in DCVax-L they should have petitioned for that for the patients' sake. But they were denied, sort of understandably. In response NWBIO asked for a trial where patients in the control group showing tumor progression crossover to the DCVax-L group. The next best thing for the patients to no control group. This was allowed.
With such a crossover mandate (or option?), I can see why overall survival, (OS), is no longer the right measure for trial success. In fact, I don't see how you could measure OS in that model. It would be unfair to DCVax-L to count a crossover patient as a DCVax-L patient if no tumor progression was part of the requirement for DCVax-L. At the same time, it would be unfair to DCVax-L to count that patient as a control patient, because if DCVax-L extends their life in spite of prior tumor progression, then you would be crediting standard of care with that extension.
What about progression free survival (PFS). PFS for the control patients that crossover is straight-forward. PFS for DCVax-L patients is straightforward. So crossover does not create a problem in measuring PFS, but if it makes the measurement of OS impossible... then how can OS be the secondary endpoint for the trial? Is it not?
Tumor DC Blocking Chemistries are Proteins?
Almost everything in biochem is a protein. But are these tumor generated anti-Dendritic Cell chemistries proteins? In one of the articles that Flipper recently circulated they are just referenced as soluble. Beef isn't soluble. Atlas protein shake powder is soluble... so hard for me to say.
My general curiosity stems from a desire to see DCVax-L as not only an exposure of the dendritic cells to all the tumor proteins, but an exposure to all the tumor components, period.
If DC's are strictly protein antigen presenting in nature, then I suppose that exposing them to more than the lysate(d proteins) would not gain anything. But if they have other functions, or if there are other immune system components in the blood that respond to other antigens that could be (or are) added to the dendritic cells, then...
then that changes what you would do after you generate the lysate. Do you then filter out everything but the proteins isolated, or do you just deactivate the lysing chemistry, and keep everything for use in exposure to the dendritic cells and or other isolated immune system components. The reason this second option seems more attractive to me is that it includes the unknown, which is usually larger than the known. DCVax-L has the distinction of addressing a large range of antigens. This second method may or may not further extend that range.
Whatever these DC blocking chemistries are, it would seem likely that is a big area of research, and there are likely drugs developed or in development to stop them, and it is likely that many of you know all about these things. The drugs blocking these factors are likely among the drugs that some of you have mentioned would work well with DCVax-L. Prey tell.
As for January News: I could swear Linda Powers said that due to delays in nailing dosing, she thought max 1 or 2 Direct patient early results in all of Q1. But I hope you are right Flipper, that some data comes in January. If so, then it would seem likely that it would be presented at that January 27 conference. Among the listed topics was early results for new immunotherapy trials. However, other topics were not as exciting.
I think a DCVax-Direct trial in Japan would be a very smart move unless there was concern about Direct trumping L.
Thanks for the caution OU71764:
Regarding the Golden ticket that Flipper gave me for the big event; Thanks for the caution. As I recall you have made efforts in past posts to caution others against over exuberance leading to irrational risk taking.
I might assume that the Phase 3 criterion of non-progression after chemo and radiation was put in place because it favors DCVax-L patients over the placebo patients. But not knowing how much it favors means that I should Do the Do (Diligence) and or be happy with a silver ticket with the implied deeper consideration of the range of potential outcomes through the event. Betting the farm in biotech is generally not wise.
But speaking of the farm; My apologies to Eva Gabor and the Ziffles. I was waiting for the opportunity to make that apology. My memory just isn't what it used to be. In fact, I don't think it ever was.
But back on the big event. I will likely reduce to a large core through the event, which will include any warrants I have left. But as I learn more about the subgroups that were likely setup in advance, I am understanding that if there is an initial big negative, it will likely be a huge buying opportunity, and having dropped my halo for the event, I might just put on my Yosemite Sam Hat!!!!!!!
Thanks again Flipper for the Golden Ticket!
If you didn't read Flipper's last post, you should. He solidly refutes the rumor that NWBO's phase 3 is dealing with a tougher patient group than their phase 1.
Good stuff!
Something to hang on to as the pee trickles down my leg during "the event".
Flipper
In that NIH article, Dr. Liau sounds confident in a future for DCVax, but the list of studies and their results include many failures, so it was difficult for me to have the same confidence.
Perhaps I automatically take an average of the results of the many clinicals described. But maybe that would be like watching that movie "Those Magnificent Men in their Flying Machines" in preparation for viewing Orville and Wilburs big test flight.
The problem is that the DCVax-L trial started quite a while ago, so the techniques are not necessarily newer than those in many of these trials. Doesn't mean the techniques/details aren't better, but they are not newer.
I suppose I could assume that many things are being tried that are inferior to prior trial techniques. That would make sense. Trying anything new would most often show worse results than the best out there to date. The failures would outnumber the successes.
Thank you Flipper: A wild ride through DCVax History.
I read the entire NIH article, and now my brain hurts. Hmmm. Good thing NWBO is close to finishing DCVax-L trials.
I will get more out of that article as I learn more terminology. This is certainly an area I could study for the duration; as an investor, a scientist, and as an interested and concerned person.
The article is a mix of good and bad news and in the end I don't walk away feeling quite as confident as I would like. However, there was one study that stood out (to me) as particularly positive.
"In a Phase I/II study of tumor lysate-loaded DC vaccination for malignant glioma, subcutaneous injections of DCs loaded with tumor lysate were administered biweekly for a total of three injections [43]. Elevated IFN-? mRNA levels in PBMCs, positive cytotoxicity assays, increased peripheral CD8+ CTLs, and increased infiltration of CD45RO+ memory and CD8+ T cells in progressive tumor corroborated a positive immune response. Additionally, this study reported an increased median survival in patients receiving vaccinations (133 weeks) compared to historical controls (30 weeks), further substantiating the viability of DC immunotherapy for glioma."
"43. Yu JS, Liu G, Ying H, et al. Vaccination with tumor lysate-pulsed dendritic cells elicits antigen-specific, cytotoxic T-cells in patients with malignant glioma. Cancer Res. 2004;64:4973–4979. [PubMed]"
This is a pretty concise synopsis of such a study. Perhaps I should assume that the detailed version of this study, or one like it, gave clues to NWBO well beyond the surface level of this article.
NWBO had to have gone into this effort with more confidence than this larger NIH article would suggest; but this article is written by the lead investigator at a prime clinic for DCVax-L.
Is Standard of Care Temozolomide Leveling the OS Numbers for Immunotherapies?
I understand that the sectioning and radiation provided by standard of care are considered important, and that even the chemo prior to DCVax-L might weaken the cancer, helping DCVAX-L to get a foot-hold. I understand that there is a required wait period after chemo before DCVAX-L can start. Makes sense because the chemo might kill off or weaken the desired immune response...
But if the standard of care chemo, temozolomide, continues throughout the trial, isn't that an awkward cycling between chemo and DCVax-L?
And temozolomide is known to be immunosuppressive right? In a quick search I find this study, for example.
http://www.ncbi.nlm.nih.gov/pubmed/21737504
"CONCLUSIONS:
Severe reductions in CD4 counts in patients with newly diagnosed HGG treated with radiation and temozolomide treatment are common, treatment-related, long-lasting, and associated with early death from tumor progression."
If I read it correctly, the study concludes that the temozolomide chemo eventually fails because it has so severely damaged the immune system.
My point being that the full potential of these immunotherapies may not be revealed by these studies, which understandably focus on assuring the current standard of care is provided.
Does the chemo continue for the crossover group?
Thanks gpb. Makes sense, but raises questions.
I just listened again to the Oppenheimer presentation by Linda again. The German hospitals have applied for "Extraordinary Reimbursement". Sounds like compensation that does not require modifying the trial model.
However, she says NWBO applied for compassionate use, but she doesn't actually say if it is for Germany, The UK, or the EU. If it's for the entire EU, and is granted, then that means big revenue for the company, but from what you are saying, Europe would no longer be contributing to patient enrollment for US FDA consideration.
But What of European Compassionate Use (or just German):
I know the German clinics applied for some kind of compassionate use status, but didn't Linda say they were waiting on a similar decision for the broader EU? I thought the EU countries were separate on healthcare... but I remember Linda describing something broader late in the application and correspondence process.
If Germany allows compassionate use, then NWBO gets paid, right? So not only are the trials free for NWBO to conduct, they make money on them, right?
If this actor that underwent DCVAX-L treatment is well known in England, then not only will that generate huge interest in enrollment, but it might help a little in any EU vote or even German vote on compassionate use.
What About A Phase 2 for Direct in Japan?
A recent article (fairly recent and referenced / links provided in this blog somewhere back there) describes a new approval policy in Japan specifically for immunotherapies. The article says they have made it easier to get approval with a phase 2 study. Iff this NWBO presentation at an Oncology conference in January is about some good early results for Direct, maybe it would make sense to start a phase 2 trial in Japan once Phase 1 is fully completed here. Phase 1 being the dosing portion.
The article doesn't mention Dendritic Cell therapies or NWBO, but they appeared to be saying that the policy applied to all types of immunotherapies. Certainly something like Direct would be of great benefit... particularly in certain regions and with certain workers. Japan is very sensitive to talk about some issues so I am avoiding that here. It would be beneficial for others to do the same. Again the article did not appear to about the issues I am alluding to.