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Unfortunately, DC's for all antigens in proportion to their population in the tumor is probably not statistically optimum. So I was wrong. But there is a silver lining.
The chances of a programmed DC finding it's antigen is proportional to the product of the number of DC's programmed for that antigen, and the number of that antigen expressed on the tumor cell membrane.
So, take 3 different antigens on the tumor membrane with the populations: (1, 5, 1). Now match that with the population of DC's created as (1, 5, 1). The chances of a DC hit on the tumor will be proportional to (1 + 25 + 1) = 27.
Compare that to just programming all the DC's as the most common antigen, the second antigen, ie (0, 7, 0). The yield there is (0 + 35 + 0) = 35. So the statistical optimum for killing the tumor for these considerations is just using the most common antigen to program the DC's.
So my argument for programming the DC's in proportion to the antigen population spread being the statistical optimum, which I said was a stretch, was more than a stretch. It was wrong.
However, in addition to the aforementioned (by others) issues of a given antigen disappearing due to mutation, and possible problems recognizing synthetic antigens for programming, there is another glaring problem with targeting a single antigen. Note that using a single antigen was stated as optimum by a self proclaimed expert on another blog. That initiated this thread.
IMUC targeted 7 antigens with ICT-107. And they acknowledged that a significant percentage of patients would not be helped by ICT-107. There was debate as to what the percentage was, but even the number the that IMUC touted was either 25% or 50% of patients that would not be well handled by those 7 antigens.
If 7 antigens is broadly known to not cover every GBM tumor, then why in the world would this supposed expert be pushing the idea of using a single antigen? So that is a huge gaff in the apparent expert's reasoning, making him far less credible. Further, the guy was using vocabulary that he knew 95% of his audience would not understand. I think that usually means the guy is not broadly smart. He is show-boating at the expense of communication. That's not smart. I thought he was saying that DC training with tumor Lysate would likely produce DC's programmed against native (un-mutated) proteins, resulting in auto-immune problems. But he ignored the fact that the immune system is known to not behave that way, and that studies were done on that issue many times by NWBO and many others, and this minor concern was proven a non-issue. Further, he didn't describe this mechanism for bad programming. He threw out a buzz-word / technical term, but with no description whatsoever.
Bottom line... he knows some technical terms, but he doesn't appear to know what he is talking about. Or, of course, he may be shorting the stock and deliberately misleading readers.
I have the same effect, but I will reply:
In spite of all the modeling for chance of early approval on the board here, I have not reviewed any statistics for more than a decade... and I never knew it that well. So my vocabulary will be limited and probably incorrect.
However, is this what you are saying?
The median PFS for the experimental group and the control will be two numbers, but the quality/reliability of that measure will be a bell curve around each of width that is a function of the amount of data collected.
So while the curves may be fairly broad at this point, if the separation of the two PFS numbers is sufficient, then the overlap of the two tails would be sufficiently small to allow approval. And you believe that if the results match the early study statistics, that those two broad curves will in fact be sufficiently separated to meet the primary endpoint.
More Antigens Better?
In addition to the synthetic vs natural antigen issue, there is the issue that it might not be reasonable to assume what the antigens are going to be. Clearly the scientist that developed ICT-107 believed they could make some assumptions about what antigens would be present, but even they believed that ICT-107 was not going to be effective for everyone.
More Antigens Better?
I want to try to logic through this:
1 Antigen, 10M DC's:
You had better pick the most common antigen.
Tumor Lysate, 10M DC's:
Assuming the cell mechanism for presenting internal proteins on the outer cell membrane does not discriminate, and or that the lysing process generates the same population/distribution; The most common antigen will be targeted by the most DC's. DC's for all antigens will be generated in proportion to how common the antigens are.
In Filter theory, the Wiener–Hopf equation shows that the best signal to noise you can get from a "noise filter" is by shaping the pass-band proportional to the signal to noise over that spectrum.
It's a little bit of a stretch... but I think it might be a meaningful analog. The same principals might say that the best you can do statistically in programming DC's is to program them in proportion to the antigen population. That is what a tumor lysate would do. That is what DCVax-L does, (given the two aforementioned assumptions).
Besides... Linda Lau apparently thought it was the best way to go or she would not have joined the team... for what that is worth.
It appears I am smothering the blog:
I will try to stay away for a while. I guess I do tend to be negative. But it is not Northwest that I am criticizing, and I am heavily invested.
But when all is said and done, if these negative things turn out to be true, I hope people get involved in trying to change them. Maybe the Million Bald Man March on Washington DC. (along with 10 million friends and family members). Someday, if needed.
Long: Let me restate it.
As I said, I accept what I have heard; that the initial SOC for GBM is beneficial for DCVax-L. The initial SOC is 6 weeks of chemo and radiation. I accept that some or all of that is beneficial.
However I have never heard anyone say that the follow-up 28 weeks of chemo cycling helps DCVax-L, and I suspect that the entirety of it does not. My understanding, which may be wrong, is that the FDA forces the entirety of the SOC while testing DCVax-L. I believe there is likely a conflict at some point, and I think that Northwest knows that and was forced to develop a very sophisticated trial to work around it.
It is known that Temodar often destroys the immune system. I read a write-up about that, and posted the link on this blog about a month ago. Obviously an immunotherapy is useless once the immune system is destroyed. The DC's don't do anything by themselves. They need a lot of other players.
I think that Northwest should have been allowed to test different durations of secondary chemo in phase 1, and I suspect they were not allowed to do so.
My guess is that these things are all true and clear to Northwest and others in the space.
If Northwest gets early approval, as I hope, it will relieve pressure on Germany to adhere strictly to the current trial design. If Germany already approved the trial design, as I believe I have heard, then that is great, but they still might be hoping for early FDA approval so they can tweak the protocol to something that makes more sense. Something like 14 weeks of secondary chemo rather than 28. Or maybe no secondary chemo. With those changes they might be able to change the primary endpoint to OS instead of PFS.
The extensive European clinicals with DCVax-L that John recently posted; the ones with mistletoe and heating... I don't think there was chemo involved. Certainly not chemo that is known to often limit OS whether the DC's are used or not.
And Provenge was not tested with chemo. The applications information states that it has never been tested with chemo.
DCVax-L is going to pass in spite of the irrational requirement of strict adhesion to the entire SOC, but only because Northwest developed a very sophisticated trial, based on PFS, to work around the lunacy.
But I am guessing. Not like the solid stuff you get from Flipper et al, but I believe this perspective is important, if ill timed.
As far as phase 1 OS goes... talk to IMUC about that. As far as compassionate use goes... not sure they are forced to follow the trial design when not in the trial. They may not have used chemo.
Hypothetical Clinical Trial:
Lets say SOC for GBM was raising the temperature of the tumor locally by 12 deg F for 10 weeks.
Then some scientist finds that in mice, an even more effective treatment is to lower the temperature of the tumor, locally, by 12 deg F for 10 weeks.
Would the required $500M trial series then be forced by the FDA into the following format?: The control group gets the tumor heated by 12 deg F for 10 weeks. The experimental group gets no treatment whatsoever.
I hope the FDA was flexible about "SOC" in this DCVax-L trial. If not, then nobody should complain about the OS not being great. I heard such complaints on the Yahoo board regarding the DCVax-L trial design. After approval... there needs to be a lot of discussion about these issues for immunotherapies.
Germany may not like the use of a placebo and the chemo regimen. Perhaps they are rational over there. Could be.
Flipper: Was the Chemo Temodar, as usual?
The Veterinary Business never made sense to me.
I remember the reports or at least blog postings about it. If it costs $80K for DCVax-L for people, how much discount would you have to allow to market it for dogs? A 90% discount would still put it at $8K for a dog. There's a market, but not a huge market.
What would have made sense is using dogs for early testing of DCVax-Direct. They could have offered that at a very large discount!
I lost a great dog to cancer about 15 months ago. Mast Cell? Something like that. Actually not my dog. I walked it for a friend who had a bad back. But I walked it regularly for several years, so it felt like my dog. She had the cancer for years before it took off in a big way. Perfect candidate for some cancer treatment. Wish DCVax-? would have been an option. But $8K... I love you Fido, but it doesn't look good.
Rene: My rationalization of the delay on Direct:
Not sure I should share this view, but this is how I stay positive about Direct:
1) This is not the best time for Northwest to have good results on Direct for various reasons. However, they would not hold onto good news because that would not be in guidelines... I don't think.
2) Direct is an injection into the tumors. Maybe it works from the inside out. If so, and if the criterion of effect is that the tumor outer dimensions shrink a certain percentage, then the tumor might show no improvement, technically, until it suddenly disappears. For Northwest's sake, that is ideally some time in the future for various reasons.
The PR Quote on 6 to 8 Weeks for the Review:
Oh well... looks like Ms. Linda Powers, CEO, Northwest Biotherapeutics did give a 6 to 8 week estimate for the review period, for this specific review, not as a general statement about typical reviews periods. Still... I am not that concerned.
"Due to the work involved in auditing and preparing the data, and conducting the review, it is anticipated that the DMC may complete its evaluation and recommendation approximately six to eight weeks from now."
I don't think the delay is much indicator.
If there was a huge delay to the review board decision, then that might be an indicator that a simple continue was less likely. However, given the complexity of the trial, and the holidays lost, I don't think this constitutes enough delay at this point to be any indicator.
Ms. Linda Powers, CEO, NWBIO, spoke about many subgroups being setup for the trial. It could be that they have to analyze all those subgroups individually.
Unsure if Ms. Linda Powers, CEO, NWBIO, was estimating the time for this review with all the subgroups and holidays, or just re-iterating the standard estimate provided in the industry. I will look for the quote and see if it clarifies this issue.
As for my concerns about 7 months of chemo... all the data on compassionate care results as well as phase 1 suggest my concern is unwarranted. Nevertheless, I emailed someone at Northwest with the question. I will let you know if they respond with anything that clarifies the issue.
So you say hell has frozen over Rene?
The Interim Review Board recommendation will be given when they finish their analysis. It is a certainty that they could care less what the conference schedules are.
That conference happens to fall on a date that is very likely past the date that the review board gives their recommendation. Northwest probably expects to discuss the review board recommendation in that presentation, but the discussion will not likely contain anything new of material significance since it is not public.
The related question remains whether it is legal to release material information publicly during trading hours or (after/pre market) trading hours?
I understand that SOC helps DCVax-L:
At least that it helps in the beginning.
But SOC apparently runs chemo to the point of diminishing returns... a total of about 7 1/4 months. And that is also the mean or median time to progression.
But if that is the point of diminishing returns because the immune system is typically starting to die at that point, then it would seem unlikely that is the optimum time to end chemo when you are testing out a simultaneous immunotherapy.
NWBO and others should have been able to test how long the second part of chemo should be run when testing their therapies. Ie, 6 weeks, 12 weeks, 18 weeks... probably not 24 weeks. This on top of the first 6 weeks of chemo and radiation.
Maybe the SOC does get modified a little for these trials. All this gloom and doom is moot if you consider the reported results in phase 1. Assuming phase 1 had the same requirements as phases 2 and 3 other than better sectioning in 3.
But if those good results came with 7 1/4 months of chemo, then they may not need any fancy PD-L1 blockers or anything else to jump forward. They may only need to reduce that last 6 months of chemo. A single parameter to optimize, slowly as they work backwards in duration. That would be a very safe study and should be allowed without controls and with paid patients after tomorrows early approval; this Friday morning's announcement thereof.
If the drop in the immune system strength is measureable in some way, perhaps they can determine the optimum time to quit chemo based on that measure.
Back to the Basics on Protocols for me:
Sorry to go back to the basics on treatment and control protocols, but I want to get solid here.
This is the key descriptive paragraph from the NIH posted abstract from the Stupp Protocol.
http://www.ncbi.nlm.nih.gov/pubmed/15758009
*****************************************************
METHODS:
Patients with newly diagnosed, histologically confirmed glioblastoma were randomly assigned to receive radiotherapy alone (fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy) or radiotherapy plus continuous daily temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle). The primary end point was overall survival.
******************************************************
So the Stupp protocol is surgery/removal of the tumor followed 6 weeks of near daily chemo and radiation, followed by 5 days of chemo per (28 day) month for a little under 6 months. So that is almost 7 1/2 months of chemo. Since after the first 6 weeks the chemo is only for 5 days back to back every 28 days, that leaves a chemo cleans time of 23 days once every 28 days for DCVax-L to be administered. However, given that the chemo is known to often eventually destroy the immune system, and progression is often at about 7 months in... it looks like they do chemo until the immune system is greatly diminished, at which point progression often begins.
So... when does DCVax-L start if this is SOC? It starts at 6 weeks, right? The treatment schedules for DCVax-L are often offset / referenced to the first day of DCVax-L treatment.
So if DCVax-L starts at 6 weeks, at least it is used for 6 months before the immune system has typically been largely compromised. But only the patients with stronger immune systems; those who's immune systems survive 7 1/4 months of chemo (and 6 weeks of radiation) will likely survive once chemo ends. So if DCVax-L still results in good numbers, as it reportedly does, when having to work with a largely compromised immune system, then that means it will be fantastic once they work out a better complementary procedure than current SOC. Fantastic, as in not just better.
It is scary that chemo continues that long for the experimental group. If it is true that the immune system is typically nearly destroyed after SOC chemo ends, then SOC should not have been required for this trial. The FDA should not be that rigid. SOC should have been modified to 6 weeks of radiation and chemo followed by only 6 weeks of the follow-up chemo. That would leave an intact immune system for DCVax-L to continue with. That is just my uneducated guess of course. But it seems apparent to me.
That deal was 4.56B per Drug in Late Stage Development.
Since Direct would be so valuable... call it late stage. The total would be 13.7B or about 45.66 X $5 = $228/share.
But Merck is now Broke. So it might have to be someone else.
Came back online to ask about DCVax-L trial details. Probably questions addressed in many posts over the last months, but I find I am not clear on these things.
I don't know what exactly goes on early on for SOC and whether SOC chemo continues indefinitely.
SOC: surgery, radiation, chemo/Temodar:
Do they try to weaken the cancer before surgery with radiation and or Temodar to reduce any metastasis triggered by surgery?
How many times do patients typically get radiation therapy?
I have seen 6 weeks written somewhere for SOC. Is that right? Is that only for the treatment group? If less time for the treatment group, then it wouldn't be SOC...?
If SOC is really only 6 weeks normally, I would think the radiation would stop first, with chemo continuing for the duration... of 6 weeks. But I was under the impression that chemo continued for much longer than 6 weeks in SOC?
Experimental Group: DCVax-L series starts 6 weeks after... sectioning? There is a required time after chemo before DCVax-L treatment. Does that mean chemo has stopped altogether, or do they alternate between DCVax-L and chemo thereafter with appropriate wait time after each chemo treatment before the DCVax-L treatment?
Thank you Rene, for underlining my point.
Were Are Missing Anderson Too:
I want to clarify what went on in those exchanges a few days ago.
Three months ago Anderson was in-putting very useful information about infrastructure in Europe and his projections on current production capability world wide as well as projections for possible rate of expansion. These same topics were the primary focus of the last 8K which was discussed heavily on this blog.
Anderson had very high expectations for company growth over the mid-term if products all proved out. He was clearly long and clearly being honest when he talked about $50 and possibly $300 share prices. Yet he got hammered a couple of times for talking about such numbers... and then he disappeared. Apparently very sensitive to negative feedback. He was accused of pumping, when he had only been sharing his opinion.
Anderson returned to the blog a couple of weeks ago with a single post. Not a controversial post, from what I remember. Then he returned again a few days ago and commented on OU's post. Very politely saying that OU was pumping. I think he should have chosen some other word. That offended OU... maybe being a little offended is understandable, but being highly offended for the politely worded statement was not reasonable. OU did not reply, but Astra jumped all over Alexander. It didn't make any sense. Astra was clearly off base. Then OU jumped in and Alexander was being double teamed. That is when I jumped in and stated what I had been thinking when I read OU's post. It was pumping. Mild pumping, and not worth commenting on, but it was pumping.
The background was this. The day before NW had released an 8K that described a 10% dilution. This resulted in a +15% stock bump because of the wording of their 8K. Brilliant! I am long, so I think that's great, however, to some extent it is dangerous to investors on this blog to ignore such candy coating... to be polite. Only GPB was willing to point to the truth, (if I understood him and the 8K correctly), that the large payments described appeared to be for money's owed Cognate, not for the forward expansion described in the 8K. What was forward was the financial arrangements for future expansion. Recent past activities had been a squeeze because there were more projects than fully agreed financing. As a result, Cognate had to work unpaid for apparently 2 or 3 months. This kind of confusion could really hurt them as they try to expand quickly, ie if early approval were to occur. Thus it was very important that no such squabbles be possible in the new forward contracts. And apparently this was accomplished. The forward aspect may include detailed planning expansion, which has it's own costs, but the big dollars exchanged were apparently for past work by Cognate.
Northwest doesn't want or deserve the knee-jerk 10% stock drop that would normally come with a 10% dilution. They don't deserve the hit because they have kept their expenses for a phase 3 trial at much lower than industry standard. Instead of trying to defend themselves, they worded the 8K to make it sound like the money was going into future expansion, though they never said that.
Because everyone is in great anticipation of the interim review, an 8K describing $6.5M appropriated for expansion got a lot of attention. I don't know how much I care about new investors fighting to buy shares over that news, but there were people on this blog somewhat duped by the 8K. The focus of this blog lately has been on the real possibility of an early approval recommendation by the review committee, so we are all a little more prepped to misinterpret the 8K that when normally would be, given that we are (we would like to think) a step above most. But GPB's analysis of the 8K was forgotten by the next day, and the blog sort floated above what was going on. A 15% stock rise on the announcement of a 10% stock dilution. That was what was happening real time, and there was no longer any notice. Even if you are fixed long, and not trading, it is ok to comment on what is going on real time when it is that large and that senseless.
So as the helium continued to be passed from blogger to blogger, Anderson finally commented. Unfortunately he used a poor choice of words with a blogger who is apparently very sensitive. It wasn't about OU. It was about the blogs overall response to the 8K.
Recall that Anderson disappeared for 3 months after being falsely accused of being a pumper. That was probably why he used the term pumper. Upon returning he is probably being carefull to not be a pumper, even though he never was. And in that vigilance, he is going to be predisposed to using the term.
OU is a straight shooter, for sure. He says what he thinks and it is not always positive. In fact, then night before, I thought he was shooting a little too straight regarding the potential for DCVax-Prostate, and I let him know that. I wasn't mean. I had said the exact same things that he was saying a few weeks ago, but I had time to think about it and regret it. So I told him my experience and asked him to reconsider while there was time to edit his blog. The fact is... NW is trying to partner or sell Prostate, and so it must be important to them. Maybe they don't think Direct will be good for prostate. Or maybe they think Direct could take much longer than Prostate to get approved... who knows. But they have been vocal about wanting a partner for prostate. In fact, Linda's recent talk in SF was almost identical to the Oppenheimer talk about 3 weeks earlier. Recall that the SF talk was announced only a week in advance, so it could be that Linda had no time to prepare a new speech. Hard to say. But notable were the few differences between the talks. In the SF talk she did not discuss the pending decision on further German government financial contributions to those trials, and when she got to Prostate she said, well, let me move on, or some such. There were many more speakers at the SF conference than the Oppenheimer conference. It may have been more imperative that she not go over the 30 min apparent window. The Oppenheimer talk went over by about 1 1/2 minutes as I recall. She kept the SF talk under by about 1 1/2 minutes, as I recall. So that might fully explain dropping the talk about German financing and Prostate.... however, it is very possible that they are in negotiations for Prostate. In fact, that was my best guess based on all the subtleties in what she did say. Tone of voice, etc.. Once in negotiations, they just don't talk about a product or deal. And Linda had brought up the issue of wanting to partner prostate in every recent public communication. This is why I was trying to be careful talking about prostate, and why I was asking OU to consider doing the same.
OU was not offended by my suggestion, but I think a little confused about being approached directly. The next day he was a little rosier than usual about all things. I think he was sort of testing the waters. Testing out the halo I had advised him to consider dawning. But again, the entire blog was breathing helium and wearing halos that day. No crime... but it did endanger some of the newbies. There were people jumping in at $5.20, $5.30, $5.40... trying to get in before the obvious eminent approval / recommendation for early approval.
So Anderson was predisposed to use the word "pumping", and OU was predisposed to pump and was really just going with the flow of the blog, trying to be a good guy and not be negative. In fact, he was just going with the flow of the blog when Anderson politely said that he thought he was pumping.
Then Astra jumped in and hammered Anderson, eventually using the F-Word, (Furstein). In fact by telling he thought he should sell, he was telling him to leave the blog. Anderson had just left for 3 months for being hammered without cause. I was glad to see him back. I like learning about company infrastructure and expansion capabilities, and I like hearing about $300 valuations.
Then OU jumped in and started hammering and insisting that this massive indignity be dealt with. Sorry, but Astra was being overly aggressive, irrational, unfair, and OU was adding to it. I don't like seeing an innocent man being double teamed. Whether that's on a blog or in the alley behind a bar. And I get involved when I see that happening. I don't apologize for that.
Maybe I OU an apology for going overboard in response to his going overboard. I apologize OU. But like Anderson, you are too sensitive. Anderson's comment was more directed at the broader blog than at you, and his words were perhaps poorly chosen. And Anderson was right about the broader blog that day. He was just being honest.
That Genentech Video was Great Flipper.
Over my head, and the presenter moves a little too fast, but it had a lot good information. I will have to digest it slowly, looking up terms, etc..
So far, the speaker almost answered two questions I have had for a while:
1) How do the Dendritic Cells tansport the information about the antigen. Ie, do they consume the antigen, and transport it (apparently breaking it down some for presentation) or do they somehow image it... ie make a negative of it's 3D geometry and ionic character...
Apparently they can consume antigens for transport back, but I don't think they always do that. On the tumor cell membrane, if they eat the antigen, it won't be there for the T-Cells to find later. Maybe that doesn't matter because the amplification of the one DC find overwhelms the statistics... but I did not get that yet. And I guess... a related question is how many T-Cells can a single programmed DC program? Probably many... but I don't remember hearing that.
2) The other question is whether the T-Cells can multiply and retain their antigen target programming in the process. He did say that they can multiply, but it was not clear to me whether the new T-Cell keeps the programmed target info. If so, that's a neat trick.
Several Good Links Provided by Flipper lately:
Heavy Duty Genentech Speaker on Immune System:
No, but don't let Big Pharma know that cabbage cures ulcers which people spend an average of $14K on to get rid of. They will team up with Monsanto to isolate the chemical culprit, and then develop a new strain of cabbage that lacks the chemistry. Then they will make it international law that nobody is allowed to plant any other type of cabbage.
Actually, what they would have to do is make the new strain a limited regeneration type. That type would eventually eliminate every other type of cabbage through cross pollination.
Not Ignoring You Jesse: But most here have seen the link.
Hope there's no trouble between you and FatCat Banker. We've had enough trouble in these parts lately.
Moderator: Please delete this post
and post #3720. We have lost a member. Actually 2.
http://www.biopharmcatalyst.com/fda-calendar/
Cabbage cures ulcers. Cooked is definitely ok. Raw is probably better but I tried cooked. I also read that cabbage juice works.
I got an ulcer during the last stock offering volatility. As in: My Doctor prescribed a prescription proton pump inhibitor and told me to quit drinking coffee.
I quit the coffee but the proton pump inhibitor was spooky so stopped taking it. Finally read about cabbage being a cure. Tried it and it worked. I am certain that is what cured it.
The Delay May be a Plot by Big Pharma.
Specifically, the makers of Pepto Bismol:]
Not sure if you should take that very seriously, but thanks for the heads up FatCat.
It would just mean other clinics starting soon.
Even if my guess was right, it would just mean an expansion into other clinics at some point. I am sure that is being setup now if this is the case. Maybe it wasn't worth bringing up.
The trial descriptions have the planned trial size and end date, with no reason to believe those numbers won't be met, other than observed slippage in early data estimates. (I think it was 60 patients and mid 2015, but I don't remember for certain.) But that doesn't speak to where / at which clinic the patients will be treated.
John: Orlando is continuing enrollment... but when I last looked just a few weeks ago there was no indication that there were any patients enrolled. The trial outline was input in the database, but nothing was filled out.
So it still looks to me that there will be about 3 patients in Houston and 3 in Orlando, and we will hear about other clinics opening soon. The trial numbers might explode, but I don't think it will be at Orlando or Houston. But I am guessing, so not to discourage anyone from getting on their lists. But if Northwest has it's own central list, I would want to be on that list also.
My guess, based on the little info I gathered was that clinics in general try to treat all the accepted experimental therapies equally, and in doing that, they can only accept a few patients per experimental procedure.
To balance out this slight negativity: I have an acquaintance with metastasized lung cancer. I have described his situation before. To the credit of chemo and radiation, he is in remission with no tumor growth for some time. However, he has scars from the radiation therapy and a large knot on his chest where the chemo gets infused on a regular basis. He has been given regular chemo for years now, and has been told it will continue for life. Today he told me that the chemo he has just changed to costs $110K/yr. That is more than four times the cost of DCVax-L.
In the most recent Fox Business News special on NWBO and DCVax-L, there was a counter view guest, apparently planted, who argued at the end that DCVax type treatments were just too expensive to be practical. That was crap. Total crap. There was another similar presentation on Fox that ended with the same type of last minute statement from one of the hosts, that nobody had a chance to rebut.
DCVax-L currently requires surgery, chemo and radiation in addition to DCVax. So, initially the cost structure I am describing is not real. However, other than surgery, it is easy to imagine that the DCVax process will evolve quickly to include less severe and expensive adjuncts than radiation and chemo, that are also less damaging to the immune system. Further, the cost of an initial dose of chemo to weaken the cancer can't be terribly expensive. It is the cost of continuing the chemo, which is expensive and will probably go away, along with the damage that it does to the immune system.
But it's not that radiation and chemo are horrible things. They apparently save lives and extend lives sometimes. And to be honest, they are not always debilitating. My acquaintance swims at the same pool where I swim, and he is pretty fast. Not as fast as he used to be apparently, but he is in much better than average shape for a 66 year old.
But radiation and chemo were not developed as adjuncts to immunotherapy. They both severely damage the immune system. In fact, I recently read that SOC chemo for GBM often eventually destroys the immune system, at which point tumor regrowth begins / the patient starts to go under. It's not just a matter of the patient getting nauseous. So I believe the true potential of DCVax and other immunotherapies have not yet been tapped. I realize that this view is not new or controversial, but there are a lot of newbies on the blog these days.
Sobering thoughts:
1) I have a great deal of money invested because I think the chances of NW succeeding are high... and I kind of like to gamble. But I would have more money invested if it were not for these sobering facts:
Knowledgeable people on this blog were also invested in IMUC. IMUC had incredible early results. IMUC executives talked openly about hopes of an early approval from their phase 2 data for ICT-107. Thus "Even NW thinks it might get early approval" isn't a very informed perspective. (ICT-107 failed it's primary endpoint... NW believes they have a better product and a better trial design. But none the less, ICT-107's failure took a huge number of credible people by surprise.)
2) MD Anderson did not build a new wing to accommodate their massive trials for DCVax-Direct. Direct is one of about 30 experimental cancer drugs/therapies being tested at MD Anderson. Flipper has some more uplifting information, but what I saw when I looked a few weeks ago did not indicate the DCVax-Direct is being promoted more than any other experimental drug at MD Anderson. (And I could not find the newer data Flipper was talking about. I'm sure it exists because Flipper is very credible, but I haven't seen it.)
Note that most clinics appear to only be taking on a few patients for the Phase 3 trials for DCVax-L. That is why there are so many clinics involved. Germany, for example, is to treat 60 patients in 20 clinics. That may not be true for Phase 1 and 2; I don't know. One would think that many of the Phase 1 patients for DCVax-L were treated under Linda Lau at the UCLA medical center... but I don't know that.
My point being that it could well be that there will only be a few patients at MD-Anderson Houston, and a few at MD-Anderson Orlando. Note that when they opened in Orlando there were only 3 patients in Houston. So that is consistent with my downplay.
DCVax-Direct is exciting. And if I had to bet even odds whether it is going to prove revolutionary, I would take that bet. But it is pretty early to get too excited about that. The old studies that people have brought up on this blog are very encouraging, but the studies that NW references are studies on mice and or rats. Personally, my guess is that they are afraid that it will work too well and are therefore dragging their feet. But that is definitely just a guess.
Beware Motley Fool:
I used the free advice from Motley Fool years ago to help me pick a stock at the bottom of the 2008/2009 crash. I figured they understood the company finance issues better than I. Not that I didn't do my own analysis. I just wanted the assurance of another opinion. That worked out. I picked a stock that was down almost 10 fold, and it turned into a 10+ bagger.
Note that if they are good at helping with financial diligence it doesn't mean that they are any good at evaluating a biotech stock which requires guessing whether a drug/therapy is going to work as much as evaluating finances.
But my warning comes from a follow-up experience. To reward Motley Fool for helping me pick a winner, I signed up for one of their expensive services. Never did get anything I felt was useful from that service. It cost me $3K. That is not the problem. The problem was they tried to automaticly renew it at 2:30AM on a Saturday morning 3 years later. Luckily my bank flagged it as fraud (whether it was fraud or not).
The online contract might have had a note about automatic renewal, but I didn't remember any such, and these days, you don't end up with a copy of the contract. That is a big step backwards for internet business. Everything is automatic renewal, and many contracts are not emailed to you, and essentially disappear when you finish filling them out.
I guess the moral is to always print out online contracts and application forms, but I am not sure the format always makes that very easy. For me the main moral was to stay the hell away from the Motley Fool.
I have wondered the same. I don't know if the restrictions on the release of substantive information forbid release during trading hours or not. It seems the PR's are usually either before or after trading hours. I think that makes it less of an issue if one person get's the news 20ms before another. Those things would matter a great deal during trading hours.
But I don't know the rules there, and have wondered the same thing.
We are still expecting the DCVax-L Phase 3 DMC interim recommendation any day. Not data, but the recommendation to the FDA.
There are a wide range of expectations on Direct. Linda Powers said a few weeks ago that she did not expect any early results for Direct this quarter. She said maybe one or two patients, but strongly implied it was unlikely.
The talk yesterday was initially billed, along with other presentations, in the general category of trial results and trial design both, so that it was ambiguous which Northwest's talk might contain. The final billing listed most recent trial results as the first topic that each speaker was to address. Northwest apparently did not present any results, based on the lack of any bump in stock price or volume in or soon after that talk window. With no PR about Direct results prior to the talk, this was not surprising since they are legally required to present significant information publicly, yet people got all excited anyway. It was kind of strange. I made some money off the irrational exuberance. I needed the money. Thank you to all who kicked in.
Go Take Your Pills OU:
"I resent the implications that I'm a pumper or that I've had a history of pumping here."
You are hallucinating. Nobody called you a pumper or said that you have a history of pumping. Report this violation dude, but I will respond to whoever I want to respond to, including you.
Sounded like pumping to me too:
When I first came on this board a few months ago, Alexander was the one that kept talking about $300 valuations in a couple years or so. He got beat up for it and eventually left the board.
Yesterday NW submitted an 8K describing a 10% dilution and alluding to expansion. You didn't claim a violation when gpb said that the new contract did not include expansion, but only laid down the financial terms for such expansion so that it can go forward. After all, that's blasphemy, right?
You are an important part of this blog OU, and contribute more than I do, but Alexander is important also. To call that a violation is bazaar. What did you eat for breakfast? Besides, it wasn't entirely clear if he was saying the PR was pumping or your description of the PR was pumping. I thought they were both pumping myself.
Alexander was so positive in all the posts I read that when Flipper came on the scene I thought it was actually Alexander with a new name. I don't know what Astro was talking about. Maybe Adam Feurstein said something reasonable for a change or something. Or maybe you have the wrong guy in Alexander. All I know is I read about 20 posts from Alexander that talked about hundreds of dollars for the future stock price before he got bashed for saying it and disappeared.
Ns: This board?
I haven't been watching any other boards lately, but when you say the dilu word in a (n effective) PR there could be a knee jerk negative reaction.
I'm not saying that Austin (was it Austin) was not warranted in being upset, but gpb made a pretty good argument that the terms were not outrageous.
I had wondered why we were not seeing big payments to Cognate. Looks like that debt had accumulated.
My recent negativity on this blog came about mostly because of a major misconception I had about Northwest's finances. I had swallowed some BS from a basher 6 weeks ago that would have influenced most people to sell immediately. Luckily somebody set me straight on the issue last week, but not before I started to get weak knees as the (likely) window for the interim decision approached.
But myself, I am back in the saddle now, especially after all the posts today by John about the success in Germany with DCVax-L or similar for GBM. Very large number of patients described and very high success rate.
But it might dip quite a bit tomorrow morning if no PR. Unless expectations are high for the presentation tomorrow.
Ou: Absolutely! A bird in the hand!
In fact, if I were big Pharma I would not wait until DCVax-L is approved, possibly next week, because that will put NW in a better bargaining position.
Ou: Prostate is much farther along and more proven at this point.
Pet Rock: They pulled that date out of thin air
is the consensus here. Northwest stated a likely recommendation within 6 to 8 weeks from the date that 66 events was reached. That window ended up being January 21 to Feb 4, inclusive.
I don't remember if anyone came up with a hard deadline... but I don't recall such. If so, it would likely have been Flipper.
The date you have is probably the best guess from the people on the site you were looking at, but they don't really know any more than we do; is the consenus among the vocal members in the blog.
DCVax-L Prostate vs Provenge.
DCVax-L Prostate vs Provenge is the more appropriate comparison, then the last comparison I regrettably brought up.
Looking from a distance... the difference is the production cost of DCVax-L Prostate being about 3X cheaper than Provenge (as most of you know). That makes DCVax-L Prostate tremendously valuable.
An early approval for DCVax-L would give NWBIO enough credibility that partners would be lining up for DCVax-Prostate, if they aren't already. Maybe even a continue would accomplish that.
The Difference Between DCVax-Prostate and ICT107.
Anybody know differences between those treatments that should be pointed out to potential partners?
There are finite synthetic antigen(s) for DCVax-Prostate? But of known high efficacy?
The difference is NWBO doesn't BS their studies like IMUC?
Sounds like the share price forward is the remaining sore point for the deal with Cognate.
If GPB is right that the bulk or all of the money and shares were owed to Cognate, and the contract doesn't really force expansion, (and he sure sounds like he knows what he's talking about) then what remains at issue is the $4/sh for half of Cognate payments going forward.
Putting on my magic halo... I would argue that Linda had to pick a lowball number to protect Cognate. They did write in the option to raise the price if in mutual agreement. If you assume Linda would be fair, then that should not bother you. It may not make sense to assume that, but it would make sense from her point of view to pick a lowball number. In saying that, I suppose I am assuming that Linda has more control over Cognate than she does over NWBIO. If so, it would be easier for her to raise the share price in the deal going forward than lower it.
The low number is unsettling because it means she is not certain of the value of the company going forward or she is short changing NWBO. But she does not control of the share price. Regardless of how great she thinks L and Direct will perform, she doesn't control future share price. Anything outside of her control has to be contained in some way, if possible. And it was possible.
So just trust her Austin! She will raise the price if something horrible doesn't happen... like WWIII or that British actor getting hit by a bus (driven by a big pharma exec) or something.
Austin: Edited: Possibly ensuring controlling interest?
with late edits:
Linda Powers talks a lot about contingencies... risk management. For patients and others this is apparently disturbing. However, it makes sense to me. If DCVax-L, and particularly DCVax-Direct are as good as hoped, there would be takeover efforts... I would think.
At the same time, in the realm of risk management, there is the small possibility that the broader markets could tank resulting in the situation NWBO was in 5 years ago. They do need more financing to finish Phase 3 for L and to continue Direct. She can't count on early approval. For years now, bears have predicted a broad market collapse once stimulus is withdrawn. It is now being withdrawn... for real. Linda would not have to be predicting a collapse, but just adding insurance in case it happens. In case funding becomes scarce at the same time that the stock price drops with wider markets. In such a scenario she would have to offer very large quantities of stock to support the company.
Wouldn't the arrangements with Cognate also benefit NWBO as a hedge against takeover given that she controls Cognate and Cognate will be increasing shares in these deals?
(In the last post I had belatedly added a line to the end of the wrong paragraph. I do stuff like that.)
Austin: Possibly insuring controlling interest?
Linda Powers talks a lot about contingencies... risk management. For patients and others this is apparently disturbing. However, it makes sense to me. If DCVax-L, and particularly DCVax-Direct are as good as hoped, there would be takeover efforts... I would think.
At the same time, in the realm of risk management, there is the small possibility that the broader markets could tank resulting in the situation NWBO was in 5 years ago. They do need more financing to finish Phase 3 for L and to continue Direct. She can't count on early approval. For years now, bears have predicted a broad market collapse once stimulus is withdrawn. It is now being withdrawn... for real. Linda would not have to be predicting a collapse, but just adding insurance in case it happens. In case funding becomes scarce at the same time that the stock price drops with wider markets. In such a scenario she would have to create very large stock offerings to support the company and would then be vulnerable to takeover given that she controls Cognate.
Wouldn't the arrangements with Cognate also benefit NWBO as a hedge against takeover?