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sharpie510,
Some of my earlier research pointed towards the levels of certain growth factors that act as scouts in the body might be a determining factor in whether a genetic mutation is recognized early enough to prevent precancerous cells from becoming actively growing cancer or not. DCVax-Direct, I believe, attempts to reverse a central part of the masking and signaling process that develops once pre cancer becomes active cancer. That DCVax-Direct vial shows us that some folks understand this.
austinmediainc,
I think most longs here are go big or go home thinkers. If you have a balanced investment approach then you just wait for the science to be validated or not. As much as we would all like more clarity, our dissatisfaction with the current state of affairs will not change anything. I see no positive contribution in terms of discussion from a public complaint by me, especially when I had predicted this sort of price action scenario was possible quite a while ago.
The current price reflects dissatisfaction with management, need for ongoing funding, extended time for temporary hold, general trend in the IBB and lack of good available funding options for smaller biotechs. On the other hand, suppose Mr. Woodford rejoins the effort, the temporary hold is lifted and Direct Phase 1 has patients that are still alive and doing well. Or what if Direct has fully automated manufacturing completed or nearly complete and approval process for manufacturing underway. Maybe the DC subset that correlates to survival is being more highly concentrated with a new stage in the manufacturing process. Lots of things can happen during quiet periods and not all of them are necessarily bad even though the price can not reflect what we can not see.
Ready4bluesky,
I think the main risk here is wondering what FDA will say about the data or any requests made before data submission. Linda said they were in ongoing discussions with FDA and the crossover complicated OS readouts so.. once the data was submitted there was a new risk to acknowledge. Data was submitted in October apparently so the report needed to disclose any new known risk since the previous report. This risk includes regulator decision making based on complicated OS results which are now awaiting statistically significant separation and quantity to occur. This would reflect the early vs late treatment comment Dr. Linda Liau made.
Sub Atomic master,
You bet sorting all this data out is hard and time consuming. They must do it because OS is unlike anything they have ever seen before in GBM. The blinded trial might be having trouble ending early by relying on PFS alone or the trial was unblinded and they are seeking approval so they are waiting on OS events which is complicated from FDA mandated crossover delaying OS events ("..doesn't really help our trial..." Dr. Linda Liau). This will complicate the approval process as per Flipper's comments.
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His "tripping factor" comment is saying IF the entire trial is marginal, and the mesenchymal subset is strong, they might approve the subset. I have seen a case of this (forget who), so have to agree with him there. But it would not be normal for the FDA to do this. - exwannabe-
You are correct but FDA needs something that works for GBM and the OS appears to be greater than 24 months here as per Dr. Linda Liau's comments in her October presentation. Her OS referrence points for survival were from newer data indicating 24 months OS possible. Accordingly, this DCVax-L protocol is benefitting patients with OS beyond this mark as per her comment about all patients apparently living longer. Besides the stronger mesenchymal results, Dr. Liau mentioned how even some proneural patients can benefit at crossover by using the right kind of chemo. I am sure doctors at all clinical trial sites were made aware of her findings.
The questions surrounding the length of time taken so far with the screening suspension and the investigation has created shaky ground for investors due to time=money losses. Linda did say she intended for the trial to go to the end, perhaps in anticipation of needing to have more mature OS data. Regulators appear to be dealing with a good deal of information, some of which may be being reviewed in an ongoing process. I would think that a co-primary OS petition would not take this long but other reviews could take up to about 9 months. Multiple reasons for this delay seem to be reasonable. Though accounted for otherwise in disclaimers, there is every reason to believe this trial will finish enrollment and then finish on or near on schedule. Safety does not seem to be a cause of concern so finishing should not be an issue. This as a minimum brings HE revenue.
vator,
One of my posts was deleted and then restored evidently because the first moderator did not recognize the correlation between CXCR4 and NWBO. It was apparently restored because another moderator made the connection. The lesson to be learned for me is that the dots need to be connected fairly closely here or someone might misunderstand. Best wishes.
For those looking for something to do while we wait for news on L, what correlation might method A vs method B have from the Phase 1 Direct trial? Feel free to share supporting evidence for your thoughts.
Ready4bluesky,
Your handle says it all. I think we are all ready. My hint does constitute a part of the risk/reward÷time ratio so I will take up your query.
Biotech investing generally is best suited for traders that work the shorter term cycles. Those who do invest in this sector absolutely need to be honest with themselves about risk over time tolerance. If this is what you want me to agree with you about I do. What I don't agree about is the need to avoid the risk and potential reward involved with any small cap entirely just because a company has an unsettling management style or strategy. As for those who have held for a while, last year was a good year to mitigate risk near the high. For those who have held like me, we still see reason to wait and one of those reasons is all about CXCR4.
For now, NWBO is priced almost at failure valuation for L as the current situation they face with an ongoing investigation and regulator review of data necessitates restraint by Mr. Woodford and others. Retail has now had the opportunity to purchase at nearly 90% off the 52 week high. Failure of DCVax-L would take the price under $1 for a while anyway but this Phase 3 does not look like it will be a total failure. In all likelihood the trial will be allowed to finish enrollment as a minimum and HE reimbursement would follow. What is going on now with regulators seems to be separate from the opportunity with HE. In the mean time we might want to look at clues as to why Mr. Woodford likes the science. Care to share what you know about the importance of CXCR4?
Time for another hint as to why CXCR4 is an important target. In adults macrophages generally exhibit a primary function of consuming or phagocytizing their targets. In prenatal to neonatal situations macrophages are principally involved in the process of creating new vascular pathways to support growth. Many types of cancer are able to signal at least some macrophages to revert back to their original function to support cancer growth with new vasculature. When this function of cancer cell signaling is interupted, new vascularization in cancer can be interupted. Guess what important and basically non alternative pathway many cancers use for this signaling to macrophages.
exwannabe,
When I referred to the idea of "stand alone" in my previous post that was not meant to imply comparison to historical norms. This concept is based on evidence derived from other clinical trials that point to this potential with DC therapy but for the most part has been negatively impacted by slightly to moderately active "placebos", too broad of a target population and definately the pseudo effect. FDA is tied to this trial by their own insistance for a cross-over which appears to have been a blessing to those who are "living longer". Now FDA must do everything in their power to learn what the implications of this mandated cross-over means. I believe they want to verify the biomarker ties to longevity, verify a solution to the pseudo problem, want to understand potential synergy better and understand MO of DC therapy on various subtypes. I believe they are doing that right now.
Some here seem to think that FDA is so legalistic that they could care less about what is at stake for patients outside of this trial even though the trial will help them learn a great deal about the science. These folks believe this trial will ultimately fail to gain approval because of trial design flaws. I believe there is enough flexibility designed into the trial and motivation from regulators and research community now to see this through to the end. That means we will at least get to HE reimbursement as a minimum (trial fully enrolled) or better. This minimum would mean another trial but with income. Better could be up to much, much better and perhaps be more in line with the production capacity ramp up we are seeing.
Koman,
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So there is every reason for the regulators to tell NWBO to just design another p3 trial with OS as the primary endpoint and no cross-over if there was any hint of OS difference in this current p3 trial. Don't blame the regulators for doing their job.
-koman-
Well yes but.. the crossover was mandated due to an invasive procedure for the placebo and active treatments. The need to retain patients for assessment of secondary endpoints (with a change to OS co-primary in mind perhaps from the .03 alpha spend reserved) necessitated the cross-over as well.
This treatment may be showing efficacy signals on multiple levels. It may show stand alone efficacy with mesenchymal GBM genotype with regard to PFS and OS, stand alone efficacy in mesenchymal phenotype at crossover in OS and potentiation/repotentiation of checkpoint inhibitors and various chemo/radiation therapies with PFS and OS. With this kind of activity possibly going on, FDA will want to figure this all out especially with the biomarker correlations to survival in hand. The data from this trial is just too valuable given that patients are living longer than a 24 month median. Living longer is the gold standard right?
Rkmatters,
Very good post regarding the rational behind possible paths forward. The one observation I would add is that even though HE is awaiting aproval to begin, there would obviously be strong demand from Doctors and patients for whom OS indicates strong benefit even if not approved outright for the entire patient population. If there is enough demand, this route of approval for usage is built into FDA guidelines. Doctors and patients need to be made aware of this at the earliest possible time so that there is as little delay as possible getting them a beneficial treatment if it can not be approved outright. I believe FDA understands what is at stake here.
Striped smut is indeed a common fungal disease found on grass when conditions are right and it is black. Are you implying that NWBO has been quietly walking barefoot in the park lately? A change in growing conditions or a fungicide should work well for the park. I think NWBO has engaged the services of some professionals for that.
Rkmatters,
That could be one of the reasons NWBO mentioned the cost of the statisticians in their 10k.
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I believe we all understand there will be some debate how to do it properly if they don't adopt a co-primary endpoint.
-Rkmatters-
austinmediainc,
I am not related to NWBO or its employees or affiliates or their employees in any way other than as a retail investor. I have seen what happens to small biotechs though when they run out of money. Have you ever heard of ENMD? You might have if you have been invested in this sector for very long. They are the company that CELG basically bought and got rich off of. That is what happens typically to small biotechs that show some potential. Would you rather be an owner of ENMD if it had been able to stand on its own or as it is now? Celgene had a good management team to help maximize the potential of their purchase but NWBO has better research partners working with them than ENMD could ever come close to dreaming about.
Linda has business development and teaching experience that investors often seem to forget. That experience makes her well suited for NWBO's next steps that the production ramp up anticipates. Either that or she has not learned from DNDN's mistakes which is doubtful given the cunning nature so often ascribed to her. Best wishes.
austinmediainc,
The issue of dilution with regard to fiduciary duty in the light of success would be put along side of the potential reward from maintaining independence from dilutionary agreements with others. The case against NWBO would be very subjective and difficult to prove.
AVII77,
I don't have the exact point of reference but if memory serves the 8 million shares had to do with manufacturing ramp up. Mr. Woodford may have insisted that the terms for issuance of these shares to him were met ie contracts in place to verify that funds he would provide for manufacturing ramp up were actually contractually owed to others doing the construction.
Turtle65,
My thoughts are here for the sharing. I shared a previous thought that if the temporary screening halt was to let the pipeline clear that there would be a potential announcement about 7 months after the halt was announced due to the 5 treatment minimum to be included in the trial results. Add a little time to confirm and coordinate with others to see if anything else might be news to announce and go from there. There might also be a different type of review taking place that would normally take 6-9 months and sometimes longer. If you read my earlier post today then you know that the prognostic indicator for benefit for DC treated patients is a significant breakthrough.
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..
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I hope it is not done the usual way this time and NWBO goes after the plaintiffs.
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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.