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doingmybest,
That is what I believe is taking so long. There may or may not be a dilema here that must be solved internally at FDA with regard to what I believe is a very data rich trial. There may have been enough built in flexibility for the trial to move to mesenchymal subtype emphasis at resizing if desired. If spectro analysis data was gathered from tumor samples beginning at some early point in the trial then that could be presented to support a look at mesenchymal subtype within the context of the entire patient group. If 28%-50% newly diagnosed patients are primarily mesenchymal this might keep PFS closer than desired but if 80%-85% express mesenchymal at recurrence then effect from treatment could be showing a clearly greater effect. FDA would clearly have trouble defending a too bad so sad decision if evidence of benefit is clear enough and PFS and OS are showing positive trends but.. there is that disclaimer about the decision being in the hands of regulators. On the other hand, PFS could be a non issue. PFS may be good enough already or the Germans may decide to allow the HE program move forward based on OS alone depending on analysis. Or, as flipper44 has pointed out, the recently identified prognostic indicator that can identify patients who can benefit from DCVax will make the wrong regulatory decisions very costly for regulator reputations. I am sure they are checking all the data for proof that this indicator is accurate. If it is.. well we will wake up one morning thankful for a breakthrough. I think AVII77's recent posts indicate that he has seen the light.
iclight,
I agree and would like greater clarity on multiple issues but the company has answered the legally required bull/bear questions to consider in their 10k and other SEC forms as well as put together an investigation team which will hopefully address concerns raised by public accusations. This team will be held to account by Mr. Neil Woodford's investigative team. So there will be a balanced approach to this process. The company leadership appears happy to focus their limited time and energy on other matters besides this type of discussion so that leaves the discussion up to us for now. Besides, not every bull/bear contention is management related but do correlate well to the long term prospects of the technology. By the way, the 2014 sequestered agreements between NWBO and Cognate could have been used by competitors to determine approximate cost of goods sold to NWBO if source of revenue mix was made known. Best wishes.
Turtle65,
I expect most news will come after the investigation results are shared and Mr. Woodford gives his input. The conference at the end of the month should give some updates about progress towards Direct Phase 2 launch and perhaps discussion about trial sites and endpoints if there are any expected changes. Phase 1 data may not be shared unless they think the timing is right with regard to their plans to have a peer reviewed article published. That should be done by now and they have hinted that the maturing data is encouraging. They may also be using their time advantage in their trials to match expected automation improvements to expected start of a confirmation trial for Direct. If everything really hinges on manufacturing then investors will be strung out for a while longer while capacity and automation are being worked on. In the mean time we wait for regulators to comment on L.
flipper44,
That change at or near the time of progression to mesenchymal phenotype and Dr. Linda Liau's observations over time with regard to DC treatment effectiveness on this subtype was part of the early digging that strengthened my confidence that NWBO was on to something. I believe that about 80-85% of GBM progresses to mesenchymal phenotype. As you have stated, not all biomarkers will become mesenchymal type but many of those targets will appear and become susceptible to treatment including migratory cancer cells, which are also mesenchymal.
austinmediainc,
Your lawsuit plan will only have a chance if the company fails. Success would lead to an argument of whether what they did was the best strategy for gaining shareholder value with it when it arrives. That would be pretty difficult to prove if share value increases significantly. Best wishes.
AVII77 and flipper44,
I have been spending time this evening trying to catch up on all the recent comments and something big is being hinted at here I think. Just for clarification, in the past TILs meant tumor infiltrating lymphocytes which often focused on T-cells and B cells amongst others. Now this terminology (TILs) mostly refers to tumor infiltrating lysate if I read the posts properly from the report. This would indicate to me that there may be some cross referencing going on here. Infiltrating lysate would obviously be in the form of activated DCs. The measure of pre-treatment TILs seems to be a reference to DCs trying to become activated by naturally ocurring in vivo lysing and perhaps the presence of other lymphocytes as well. This language appears to be pointing out or perhaps even bordering on attempting to confirm what was noted in the Direct trial about patients with a certain type of DC population prior to treatment having better outcomes. The other hint in all of this is that improved DC migration matters and this relates to the low dose, multiple injection site protocol being used for the Phase 3 trial which was not used in the earlier trials referenced. The reason patients might all be living longer is that the obvious best options for patients with regard to observed synergies between potential additional resection, Temodar, DCVax and checkpoint inhibitors can be used at crossover. Treatment patients have the potential initial benefit of chemo/radiation plus improved dosing regimen as well as the added dosing and same options at recurrence as SOC vs what patients from earlier trials had.
The take away here for me seems to be that DC activation subtype as well as dosing and synergy from options available at crossover are making a big difference from what has been seen in previous trials.
flipper44,
Thank you for the related posts you put up recently. This is a critical piece of the derisking puzzle for all shareholders.
Turtle65,
Your comment, "Totally agree... It is to do or die!!!" just reminded me of another quote. "Ours is not to question why, ours is but to do or die." We either believe cause and risk is worth going through the process for or we don't. We are where we are now and I am glad you have made it past the point of lament and are simply stating realistic expectations with regard to the process. I am also glad someone chose to risk it all for all of us almost 2000 years ago. Remembering this helps me find balance and put the risks I take into proper perspective. Best wishes.
sentiment stocks,
I think Ready already knew this or should have as this topic has been thoroughly discussed. Your post is a good reminder for those who have forgotten or are new to this board. I would like to suggest some sort of condensed point counter point discussion sticky for all the bull/bear points of contention. This would help newcomers get up to speed quickly and act as a barrier against repetitive positive or negative posts that don't line up with what is known or have something new to add.
vator said..
Quote:
I hope it is not done the usual way this time and NWBO goes after the plaintiffs.
-----------------------------------
I say the darkest hour is right before dawn and I don't think NWBO will be in any mood to settle this battle with a slap on the wrist to the perps when NWBO's day comes. Success would provide opportunities for major changes to be made with regard to SEC oversight and enforcement and perhaps better financing opportunities for small cap bios as well. Imagine all the investors who lost money suing these guys and others suing for opportunity loss if the dots can finally be connected.
Pyrrhonian,
I think the temporary hold was placed on initial screening only. I am pretty sure that I read something from the company stating this. My memory generally serves well but I'll go back and check if someone else can't confirm before I get back to this point.
flipper44 and Rk,
Wasn't surgery at recurrence, if deemed appropriate, already written into the protocols and vaccine permitted to be made from it? If not, this would be a very appropriate or even critical step to take. Good catch Rk.
hopeforpatients,
Hopefully Mr. Woodford has learned his lesson. I think the saying is "Don't bite the hand that will feed you into old age" or something like that lol.
Evaluate,
Hush, hush, huussshhhhh. The shorts are watching..lol. Thanks for the heads up. Best wishes.
flipper44,
I agree that it is too early to judge motivations behind what seems to be a lack of inclusion of pharma validated DC therapy effect from the AGILE and Moonshot programs. If there is a sense of desperation by big pharma, though, this "coincidence" will be quickly understood as a manifestation of it if validation of L by regulators is not immediately embraced by these programs.
highwayman4life,
Thanks for the expanded rational and clarification behind the comment I made to Rkmatters. This may help others understand why I think Mr. Neil Woodford likes the science (as per your explanation about L and the potential for Direct) and the built in flexibility this L trial has built in to make adjustments while learning and for the "just in case" scenario. Best wishes.
sentiment stocks,
Thank you for the over and above effort to get validation from reliable and experienced sources on a topic some investors may have felt vulnerable about. Optune is not currently SOC and will not have an impact on a DCVax-L decision especially if current time lines for trial completion are kept the same.
flipper44,
Seems to me that moonshot and others are last ditch effort to get a ahead of DCVax-Direct. No mention of DC therapies even though they big pharma has shown DC potentiation of other therapies.
Rkmatters,
As to the built in cushion for their screening halt delay I would say this is either odd and there will be another delay or boldly confident that the bases are covered and a favorable resolution is expected by October. I have stated my belief that protocols may have mesenchymal GBM covered. The resizing may even have had something to do with this. If NWBO kept biomarker records for all patients screened or nearly all patients screened, as I suspect they might have since about 2011-2012, then blinded analysis and randomization based on patient characteristics is possible if the company has remained blinded to data. Remember that little hint about data being submitted regarding screening criteria a while back? I think regulators have quite a bit of information on their plates right now.
Rkmatters,
I share your opinion on this but it is also common courtesy to acknowledge those who make statements you agree with. In Adam's case there are professional standards to uphold and that means even more than common courtesy. Taking what someone else has said and attributing that to yourself, even on a message board, does not reflect the implementation of either common courtesy or professional journalistic standards and this is reason enough to be called into question is it not?
Rkmatters,
I would think that Les mentioning Pyrrhonian is "bizarre" under normal circumstances. There seems to be nothing really considered normal by all sides with regard to NWBO when it comes to public commentary by anyone though. The fact that Pyrrhonian was quoted verbatim by "Adam", from a response to me on SA that "Adam" did not credit him with when used in a response to another poster here on ihub, kind of puts Les's comment in perspective. If the DMC chair can denounce Adam then I would think that Les might be doing the same via a possible surrogate voice he is using.
flipper44,
Your line of questioning is correct. RNA technology seems to hold greatest promise where RNAi (intereference) technology works to help block reproduction of faulty proteins. This is specific single target technology for diseases like MS. The multi target diseases like cancer and HIV might both be able to be managed by drug cocktails like are used for HIV but are probably best controlled by immunity. This comes from breaking down, blocking or reversing bariers or their sinals, attacking targeted non self antigens and then developing long term T and B memory cells. The immune system can be trained to do this without knowing all the specific targets which explains the hope placed in immunotherapy. Memory T-cells alone still need to get past Tregs and any other established bariers to targeted antigens like are found in solid tumors. There is a possibility that engineered T-cells plus additional therapies can be used to eventually create this same effect, DCs by themselves can be trained to create the environment for this to happen.
Pyrrhonian,
My last post was indeed unclear as to my thought process. First, let me say that I do understand all about post hoc analysis and that using post hoc data is not at all what I was aiming to suggest but perhaps came across that way. Secondly, I also understand that until there is clinical proof, evidence can be extremely positive but is not sufficient. This means that SOC comparisons, that lead to earlier deaths than "evidence" might suggest treatment arms would produce (OS treatment benefit), are many times necessary to obtain this proof. This has been one of the main ongoing debates here regarding PFS and OS.
My hope from posting was to suggest, as others have, that PFS might be good on its own. Just to be sure for the trial's sake, though, I wondered if there might be room for NWBO to amend the protocol with regard to mesenchymal GBM. I have not seen the complete protocols nor the ammendments as exactly written out so I don't know if the mesenchymal group was ever written in for potential analysis. My due diligence suggests they may have been accounted for at some point in this very long process but I can not be certain. If they are being accounted for, I thought NWBO might have the option to potentially reduce trial failure risk by submitting only their best open label and preclinical evidence. They would have about 100 mesenchymal patients and .03 spend to work with right? My question is could they make this work? I don't know for sure because I am not a statistician but if they have this option to consider, so do we. I am not a clinician either but with all the protocol changes that have happened in this trial, I thought this was a change that others were aluding to even though I had read some comments stating that this type of change would require a whole new trial. I thought perhaps these comments insinuated that the reserve spend was large enough that a new trial might not be necessary. Sorry for the confusion. Best wishes.
Pyrrhonian,
That is a possibility if there is no real or only minimal benefit being seen from DCVax-L. If there is stronger benefit for PFS but OS separation is being delayed by crossover, then to do as you suggest and have no crossover would mean FDA is willing to knowingly kill people to make NWBO prove that it can demonstrate added OS benefit in this setting. Ethical dilema big time. They would find another way to get what they want without putting patients at risk especially if mesenchymal GBM is responding exceptionally well as Dr. Linda Liau mentioned and multiple studies have suggested.
Quote:
"Exactly." flipper44
Followed by mesenchymal GBM knocking out of the park! Manufacturing capacity might be an issue if off label use is expected to create immediate additional demand for treating other mesenchymal cancers right?
flipper44,
Do you have a feel for label extension time lines and off label use demand ramp up if L is approved? Just trying to attempt a reasonable manufacturing ramp up capacity time line that regulators would find acceptable.
john1045,
Thanks for you and TC keeping this info at the top of the board.
highwayman4life,
Unfortunately the court just let VICL get away with much the same thing. This case seems to have more connecting evidence but the powers that be like the system the way it is so only very clear evidence will ever be able to have any effect. Hopefully this is being brought together now. There are 3 very large fraud cases being investigated right now according to an article I read a while back. One of them is bigger than the Madoff case. The question is whether or not enough public outcry will occur to create any effective change. I hope there will be.
OUCH! THAT'S GONNA LEAVE A MARK. FBI GUY?
Poor Man,
The same thing happened with VICL. The courts have decided it is buyer beware. If you take anything away from this it should be that you must always, always, always balance out your risk and hang out with people honestly looking for the truth to get good imput from both sides of any position for or against. Best wishes
Ready4bluesky,
I understand your concern and a case would need to be built that there was intrinsic value that was being deliberately devalued by those seeking to obtain it for themselves at a below market value. Based on my research, I actually think I have enough scientific evidence to support the idea of high intrinsic value if such a case were to be made in court. I also think that Mr. Woodford and others might be able to do the same only much better so there are checks and balances here. Based on my understanding of who Linda Powers and Les Goldman are though, that scenario would never see the light of day. UCLA and Dr. Linda Liau could also make things difficult as could the other research hospitals that currently support her. There really is no incentive for privatization unless all these institutions would give Linda support to do this as a last resort to get beneficial treatments to patients.
There are those who have been hardened by the cold reality that experience in this world system has provided them to the point where there no longer seems to be any good left for them to believe in. Linda Powers will do what she needs to do to get this to the finish line. If she can't get the help she needs from those who will support her effort publicly, she will take it home herself but that is not how she or cancer patients can benefit the most.
Pyrrhonian,
You know I am in to the end even if there is a reverse split again but will consider any hypothesis you have as to why I consider CXCR4 to be so important to my investment thesis. Best wishes.
Rkmatters,
I have found that good investing or good science always benefits those who can find the best premise to begin with. I searched for years looking for a company or companies that were focused on multiple targets and working to reverse immune system failures after originally investing in CELG back in the late 90s. I found IMUC and NWBO and considered CLDX and STML. As I continued my research I chose the company with the better science with regard to my premise. I parted with IMUC with a profit and began to invest more near the lows with NWBO. My initial research gave me some really good notes which Steven actually triggered me to go back to and research more with regard to CXCR4. He was not even discussing NWBO with that trigger post for me but rather ischemia in damaged heart tissue and a product that helped repair it.
By the way, AVII77 is right to bring up the possibility of a reverse split as Linda has obviously planned for it if necessary. I will repeat again for all to hear that as long as the NWBO house is divided with regard to Linda and Mr. Woodford we must be ready for scorched earth tactics and that might mean a reverse split. Be prepared. Best wishes.
exwannabe,
QUOTE:
"BUT changing the endpoints always add to the negative list wrt the trial being run well." exwannabe
That is one way to look at the process but the reality is that science is about learning and a good trial design allows you to learn and adjust. When you can no longer adjust you either have something or you need to start over. One look at all that has been learned over the course of this trial and how NWBO has left options on the table to be able to navigate through it all and you can see why so many believe this company is either the best sham ever or a model for future clinical trials to follow if successful. Best wishes.
DoGood DoWell,
Now you know why I suggested to be ready for a scorched earth policy and why Linda sought more financing before this next move. Whether it comes from Mr.Woodford or not the appearance of division is being used to force a reply of support for NWBO or help assist in support of any upcoming negative action taken. He can try to use his reputation against hers to gain leverage. Linda would use his demand of using Ondra against him in that case and expose his past "active investor" activities to any uneducated investors to balance the scales. Like I said before, I hope everyone is ready for a scorched earth strategy. Having some dry powder is a good thing right now.
Koman,
NWBO does indeed have a patent and a couple of the posts Evaluate put up on the board will give you clues as to understanding it's importance. It takes some digging and a little bit of fitting pieces of the puzzle together but it goes a long way in explaining what we have seen from Direct so far and why I expect Phase 2 to do exceptionally well. They want automated manufacturing ASAP because if what I think is happening really is what is going on, it is the single biggest limiting factor for this company right now.
AVII77,
I understand your concern about the psPD patients getting into the info arm and the info arm data being potentially reflective of this, however, this should be balanced out by trial design in the Phase 3. For every SOC psPD patient that potentially could be mislabeled a progressor and then get treatment, there should be 2 of the same from the treatment arm that received the more timely treatments and would be expected to event later, especially if this trend is seen more in mesenchymal GBM as per Dr. Linda Liau's comments. If the ratio of events correlates well to higher numbers of mesenchymal biomarkers and methylation as Dr. Linda Liau has alluded to then PFS benefit has a very good chance to be well established. In this scenario the only confounding data would be coming from .33 of the psPD crossover population. If Reefrad and you can agree on the scan interpretations, I believe other expert radiologists will, upon review of all the data, be able to agree as to what was actually happening and when. I also believe that the benefit will be ascribed to treatment and not separated from it. Then, when they look specifically at the mesenchymal GBM patients, the data should really stand out both with PFS and OS. Either this is true or Dr. Linda Liau is misinformed. My money is on Dr. Linda Liau being right.
austimediainc,
Just pointing out that you said you sold your shares a while ago which preserved some liquid equity and have stated that you are willing to go the distance with your warrants. You have a thought out plan. Everyone should have a thought out plan and not just be hoping for the best or expecting the worst without one. Best wishes.
AVII77,
Ok, I understand post trial data analysis gets the boot. That is what happened to Stimuvax. I am talking about a prespecified and accounted for subset in this trial for which you yourself said there was a .03 spend left out to work with. You have guessed at how it is being used with regard to an endpoint change. Is there an alternative here with regard to mesenchymal patients that you haven't shared yet?
Poor Man,
That is correct and Mr. Woodford might also be classified as an insider as an owner of more than 10% of the company. Kind of makes you wonder why the "left out" information is being used to try and steer the thinking away from the truth here. This argument was brought up on SA in detail before. No ifs ands or buts were left to discuss.