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Rkmatters,
Maybe that small, still voice after an "I've seen this before" moment? "You've got to know when to hold em..." By the way, "I'm goin down to the river, down to the river..." Best wishes.
DoGood DoWell,
Mr. Woodford's terms were at $5.50/share. NWBO's debt owed to Cognate was to be settled on the same terms and not more favorable terms than his as part of the financing deal. If options and warrants owned by NWBO/Cognate/Toucan eventually need to be converted to maintain voting control and Linda Powers and company can not convert enough because they are low on cash, this would give someone like Mr. Woodford an outside chance to take control. Before he or anyone else would do that, he would want key patents in an accessible position and he would want Linda's friends stretched financially. The value of their shares has dropped substantially so their borrowing power has dropped as well. Are you ready for a scorched earth attempt if it should materialize?
Rkmatters,
The way these collaborations are being set up seems to be an ideal way to test checkpoint inhibitors and perhaps engineered T-cells against one another. I may be misunderstanding something but each group will apparently test in 3 cancers and I would guess that Direct will also be a solo comparator against each product since it is being improved upon for Phase 2. I think they could enroll these trials in 2 weeks if they were ready and wanted to.
flipper44,
I'm pretty sure that the scientific advisory board will be carefully considering best strategy for endpoints and protocols, time frame for treatments and perhaps how to effectively alternate them to achieve optimum immune response and disease control based on known MOs and cellular cycles, and use of best predictive measures of response like the UCLA model. They will also look for the best readout measure(s) such as iRANO. Mostly, though, they represent a high profile validation of the science.
Rkmatters,
It's a good day for the future of cancer treatment. Patients need this treatment to get here yesterday though.
Always watch for how the price gets squeezed down when somebody big wants to load up. Best wishes.
flipper44,
They could announce a special convening of the board as long as sufficient advance notice is given to all shareholders so that they are aware that a vote will be taking place or they could ask for NASD regulators to simply allow them to put this vote on the agenda of the next annual meeting.
Pyrrhonian,
Mr. Woodford appears to have signed an NDA or is in a similar situation if considered an insider. He also has an obligation to his shareholders that must be fulfilled and part of that is being done with his investigation and not financing NWBO until his investigation report is published or he at least makes public comments about its findings. This is "professional" behavior.
Now let's consider the various forces at work in all of this. Let's assume for the sake of argument that there are only 2 extreme takes on Linda Powers' motivations. The bear argument is that Linda is only in this for herself and she knows that DCVax-L will fail and that DCVax-Direct is no better than grapefruit juice. The bears believe she has known this for at least 3-4 years (history of negative articles). The extreme long argument is that Linda Powers has 2 major long term goals for NWBO and they are to get DCVax (which she believes works) approved and to maintain personal control of the company. These longs believe the 1st goal is not left to chance if she maintains control of the company and that investors and traders who are waiting for validation of the science will be well rewarded when that day comes. With these 2 positions in place let's look at what happened last year.
NWBO was supposed to be in the process of failing as per the April 2015 puts that you are well aware of. The bears had been on a roll until Mr. Woodford became involved and put a monkey wrench into their time table. Mr. Woodford it seems had plans of his own which did not necessarily align with those who had been glad to see the stock price collapsing, nor with Linda's later on when the rift occurred. Mr. Woodford stated that he liked the science but remember, the bears stated case is that the science does not work. Bummer. Mr. Woodford had an interest in AZN, which is a British company, but has since sold that position after the Phase 5 report came out and his comments gave it legs which led to a rift with Linda. Even before Phase 5, the stock price had been in decline and so Mr. Woodford spoke with company management to satisfy his concerns. He stated nothing untoward was going on with regard to the company or its trials. So what forces were at work that had him so concerned in the first place? Evidently normal market shenanigans that he should have been aware of because he did not start an investigation at that point. Only after his embarrassing disclosure that Phase 5 had made him aware of something that he was not previously aware of did he start a public rift between himself and NWBO. So here we are, waiting for his report to be published or an all clear public announcement. Linda will not publish her report first because it is his move. I suspect Mr. Woodford will make that move if he is forced to by price action or at his convenience when the science is validated. By the way, the price action can be controlled by those extreme bears with Mr. Woodford on the sidelines. They need to be careful though, because Mr. Woodford might be leading them into another April 2015 type trap. Let's see when the next financing takes place. Musical chairs.
iclight,
As I see it there are 2 potential manufacturing issues. The one with regard to the PIM approval is related to expected volume from "early access" patients. This might be a low end to high end demand being expected by regulators. If they expect high end demand then production must be approved at or very near commercial level capacity before approval will be granted. The wording "able to supply the product" seems simple to do as your example suggests but the reality is that there is an unmentioned and expected demand supply level that must be met before approval will be granted. This is why we are witnessing a manufacturing ramp up in 3 countries. This L manufacturing ramp up may also be a clever smoke screen for Direct manufacturing ramp being done side by side. This would be a very clever way to surprise those who don't like surprises. If Direct manufacturing is up and running before the trial starts then how long would it take to get approvals and become commercially available? Just a thought.
The other manufacturing issue that might affect the trial and HE negotiations is a potential manufacturing change request related to producing more vaccine from the same amount of tumor or utilization of UCLA's screening technique is a non manufacturing twist to all of this as well. The manufacturing issue would require an equivalency test to gain approval and Germany may have requested this in relationship to the HE reimbursement negotiations to help keep cost per vaccination down and or give patients a better opportunity with more vaccine produced. All regulators would need to be on board for this to happen. In the mean time, OS eventing continues in hopes of seeing a clearer separation between early treatment vs late treatment patients.
iwasadiver,
"You've got to know when to hold em, know when to fold em, know when to walk away and when to run. You never count your money when you're sittin at the table. There'll be time enough for countin when the dealins done." Kenny Rogers from The Gambler
iwasadiver,
If there was ever a trial that patients might be willing to pay to get into, the Direct Phase 2 would be it. There might also be some understandable special interest in what is going on by those known for making documentaries. If I were Nat Geo management (I am not), where one of my own was living testimony, I would certainly be interested in following this technology very closely.
antihama,
Manufacturing is an issue for the Europeans and the PIM approval process. The second part of the approval depends heavily on manufacturing standards and commercial production capacity. Best wishes.
Rkmatters,
Taking what you say one step further, what if iRANO was asked for as part of a validation process of immune response in conjunction with the UCLA findings that correlate biomarkers to survival benefit? Might make things interesting.
eagle8,
I am pretty sure that Mr. Woodford would release his report one way or the other if a reverse split looked inevitable. This would not happen for at least 3 months after the stock dropped below $1. Release of his report can help clear things up almost immediately for better or for worse and Mr. Woodford's investors would be quite alarmed if NWBO ended up in a reverse split situation especially if he was in position to warn investors ahead of time and did not do so. That would leave him with a great deal to explain to the satisfaction of those investors and I don't think saying "oops" will do.
Rkmatters,
That was again a very well thought out post. As far as improved SOC is concerned, Dr. Linda Liau pretty much covered that by saying standard treatment can move SOC up to 24 months OS. I expect to see a little less (21-24) than this because not all sites are UCLA caliber and remaining tumor burden will be mixed to some degree. We need to also consider that Dr. Liau's comments about not seeing the required number of events might be taken 2 ways. One way is that this referred to PFS events which would be a strong case for possible manufacturing holdup as cause for delay if there had not been an intervening DMC recommendation given to the company without her knowledge. The other way to understand her comment is in light of the early vs late treatment OS comparison she said the trial had come down to. In this case our referrence point is 24 months OS being moved up in considerable fashion and comments made by management indicated that they had some good mature data on OS already. These comments obviously point back to the vanguard group. For me, this indicates that FDA may be quietly waiting and watching for matching results with the vanguard from the newer patient population and the smallest group results total necessary to reach statistical significance with a high degree of confidence. They may also be considering the newest findings from UCLA with regard to those most likely to benefit from treatment and any ethical issues surrounding large subgroup populations showing benefit if the entire group misses by a little. Add in all the synergies that are probably showing up and you have an overflowing plate. Plenty of things to ponder here. Bottom line for me is that SOC can not claim benefit from increased TILs caused by DCVax and CIs only help a small group of patients without additional TILs in the area. If all apparently are living longer than 24 months by a significant margin then DCVax will get the credit and the wider the margin the sooner they get the credit with fewer patients accrued.
Rkmatters,
Your explanation is sound here. The only thing I would add is that at some point all patients living longer would be ascribed to treatment so there would not be ad infinitum.
flipper44,
These are good asumptions. We should also compare these assumptions to the most neutral long argument from Rkmatters then,that PFS benefit is minimal but that OS could demonstrate significant benefit. Based on a most likely range of enrollment and event rates that led to the 66 events triggered in 12-2013 and comments by Dr. Prins and Dr. Liau that DCVax works in some subtypes better than in others, the treatment vs SOC PFS separation could be closer than originally expected from the Phase 1. We might also expect a strong separation in benefit from those who respond and those who do not based on the comments we heard.
flipper44,
The CD3+ T-cell count seems to reflect immune response level while neutrophil count seems associated with immunosuppression. When immunosuppression exceeds certain values then this becomes reflected in longer term prognosis with treatments currently available. The hope here is to turn this indicator almost upside down with immunotherapy mono or combo treatments. Remember that these indicators correlate only to current treatment regimens and this correlation does not necessarily predict correlation to all possible treatment types. You expressed this in expressing the hope that improved treatment schedule with L could lead to better outcomes for most if not all patients and I believe this to be the case as well. I also believe that earlier administration of L as a primer could be helpful as well since synergies are known to exist between immunotherapy and chemo/radio therapy potentiation. Less cancer cell repair would happen after surgery and perhaps additional exposed antigens could be picked up as well.
afford567,
Sorry I didn't respond sooner to your 1st post. flipper's response is sufficient but I'll add that the University of Pennsylvania and others were showing signs of success in blood born cancers about 4 years ago. A little girl they treated with just days to live went into complete remission. The reaction to the treatment was so strong they had to give her an immunosuppressor to slow down the response so that the reaction to the treatment would not kill her. This newer treatment you pointed out is a great upgrade and shows the promise of engineered T-cells in blood born cancers. Cost for many of these treatments can be an issue, though, as well as side effects but this article seems to point to a chance at better control of both these issues especially safety.
Doktornolittle,
DCs, if properly activated, can manipulate their environment to get antigens to present themselves that would otherwise remain hidden. With DCVax-L they must first present the antigens they picked up from the lysate to T-cells in the lymph zone so that these T-cells have all the neoantigens and hidden antigens that DCVax was able to pick up. This is why saving all the resected tumor for lysing is so important since individual antigen types are not necessarily evenly distributed throughout the tumor. Once these T-cells are properly targeted then they return to the site of active immune response signalling which is done by the DCs. If the DCs move off site too quickly the tumor environment changes which allows the cancer signaling to hide critical targets from the T-cells again and signals all is well. This is why flipper44 and I believe the dosing and treatment schedule is critical to the success of DCVax and the Phase 3 trial is better on both of these counts than in previous trials.
flipper44,
I know you are aware of a vast majority of what I write about. I just like to respond in a way that may be helpful as a reminder to others. I hope that this style is not too bothersome but if it is I'll be glad to change it. Thanks.
flipper44,
Dr. Linda Liau explained last year how to make DCVax-L more effective for ALL patients. Her understanding most assuradly has been passed on to all doctors involved in this study. Maybe that is why she mentioned not reaching a preset number of events since they are now comparing early treatment vs crossover treatment. If you can't end the trial because secondary events are not happening as expected then that is not good for the trial but it is really good for the patients. The unfortunate part of this study is that treatment stops after 3 years and those who might otherwise have benefitted greatly were left to event without treatment if they were long surviving SOC patients. This is what appears to have happened with Rkmatters nephew. I give her the highest praise for sticking this out through thick and thin in the hopes of seeing this work.
flipper44,
Remember that study from way back when that confirmed that intratumoral DCs modified the tumor microenvironment? Well, DCs by their very nature do this in response to inflamation signals. Cancer just happens to be able to get them to move away too soon or hides critical targets from them en vivo. DCVax gets its cancer prep elsewhere. Best wishes.
flipper44,
Higher level of actively circulating lymphocytes = greater response rate to DCVax-L? Indubitably as long as there is a check down on Tregs by sufficient cytokine release or CI.
flipper44,
Ok, I see where you are coming from and completely agree. Lymphopenia with regard to Tregs is a good thing and Tregs may be slightly delayed in their rebuild which would give DCVax-L a little time to work with. Thanks for your thoughts.
flipper44,
I forgot to mention that with proneural those older targets are basically still the same and they are protected from an immune response much better which is why the checkpoint inhibitors are needed. If at crossover patients are also receiving checkpoint inhibitors we have a secondary endpoint issue because all patients might be living longer right? Maybe that is why there has been talk about collaborations?
flipper44,
Most of those preexisting lymphocytes that are circulating are probably for earlier accessible targets and not those that are best conserved, most critcal and protected by tumor defense mechanisms. Lysing exposes otherwise protected antigen targets hence the repriming of older and initial priming of newer targets.
Rkmatters,
You used the word "regrettably" when discussing Ondra's discovery of Katherine Wolf's conflict of interest. Ondra may end up regretting not vetting Katherine Wolf before they sent her in. There are very good investigators doing the work necessary to determine what links there may have been and companies can be found negligent because of their employees as we all know.
By the way, a non disclosure agreement can be looked at as a risk/reward proposition. What are the typical risks here if Katherine Wolf has no prior run in with the law? What might be her reward?
flipper44,
Those circulating lymphocytes take time to build up because lymphocytes are first drawn to the site of inflamation, where they become educated for the fight. Then some develop into immune memory cells and go into circulation. As the fight begins to end locally circulatory immune memory cells build up systemically. In solid tumor cancer, all of this is predicated on being able to control the localized tumor environment long enough for this full process to occur. That is unless you just want to unleash an out of control engineered T-cell response and hope for the best. Best wishes.
Rkmatters,
I agree with you about innocent until proven guilty but many, myself included, have very strong suspicions that Katherine Wolf was attempting to cross a line that a "reasonable" aid, remember Ondra was sent to aid NWBO, would not cross. This tripped a trigger for Linda. This is where you disagree with Linda's account and believe that Katherine Wolf was just prying into areas where you believe wrongdoing might have been occuring. This is your perspective superimposed upon a situation where Katherine Wolf had an undeniable and almost unnoticed conflict of interest based on her work history. You have not convinced Mr. Neal Woodford otherwise and she was indirectly under contract with him. Case closed.. unless you intend to try and link Mr. Woodford to some kind of involved investor activity.
If Linda's investigators can establish a case for malfeasance with intent she will teach someone a very hard lesson within the time frame allowed for a case to be presented. No need to rush into that right now and maybe leverage is more important for several court cases that NWBO and Cognate are involved in anyway.
You have come to believe that Linda and NWBO need to be investigated for wrongdoing. I believe she didn't act in a forthright manner soon enough with investors because she thought she could run a public company like a private one. This is now being addressed by having been forced to do an investigation while Mr. Woodford does his. What Ondra was supposed to do the investigations will now do. This is what Linda is guilty of and we are all now paying the price even though she may feel what she did was to protect the company and investors from unwarranted investigation.
I know Linda has protected some of her gains very well but her net worth has suffered substantially during the last 8 months as has that of all longs who have held. Linda is NWBO and Cognate and Toucan as well. Wrongdoing would not leave her or companies she is connected to unscathed. I am sure she is well aware of this and has no intention of dragging her family into the fray either since they are also connected. Best wishes.
flipper44,
I agree with your conclusions. DCVax-L (primer 1) as is will be used to prime an immune response to the newest neoantigens. Then the responding T-cells will be harvested and cloned for use as an adjunct combination therapy or neoantigens will be identified, separated and those that cause the best T-cell response will be presented to DCs to create DCVax-L (primer 2). The harvested T-cells approach is being tested now and results should be known within 1 year. My understanding is that the neoantigens primed DC approach has yet to be tested.
sentiment stocks,
Thank you for taking the time to transcribe this part of Dr. Prins presentation.
Rkmatters,
Another very good post and I am sure that more than one person is looking into this. No doubt that Linda walks a very thin line here but when NWBO turns the corner, I doubt she will want all the negative connotations surrounding her actions following her in the news all the time. I believe validation will change business MO. Spotlights tend to do that especially when prestigious organizations are involved. Best wishes.
chinatown1980,
I entered NWBO shortly before Larry Smith first recommended it. As you well know it went from there to the $12.50s at which time I could have exited. I did not exit because my strategy has been to accumulate over time near the lows until the potential of this company is realized. I am well aware that others build their share count and protect their gains differently. I work on building my confidence level over time with research. If my confidence level decreases due to changing science or other critical circumstances then that is my defensive sell signal.
As far as lessons learned.. well I have found that patience is a virtue that is often well rewarded. Isn't there an Woodford investment fund that kind of hints at that too?
chinatown1980,
Does e=mcc help explain our existance? If it does, then maybe what you read about the Sawston project can help explain Cognate's relationship to NWBO better. You have one of the more interesting puzzle pieces. Let's see if you figure out where to place it in the puzzle.
chinatown1980,
That was Direct, multiple tumors injected. Multiple tumors injected creates greater overall chemokine and TIL response and increased mobilization of systemic immune surveillance.
vator,
They are just following the script they use with companies they target. Negative press, bear raids, personal attacks on supporters, leveraging shares for board influence, lawsuits, nuanced regulatory influence to disrupt and delay. Couple this with a few mistakes which are bound to happen with a small company and credibility with investors begins to erode over time. This becomes reflected in the share price.
The investigation by Mr. Woodford insured a low share price would be achieved. The only way this turns all the way around is a favorable regulatory decision and Mr. Woodford's very public approval of NWBO after his investigation is complete. Linda will not announce her investigation results before he announces his or they do so jointly. She is too smart to let him have the final word and permit any chance for her investigation results to be doubted. This may of course cause consternation amongst those who expected at least 90 days to be a fixed point in time. Best wishes.
DoGood DoWell,
Exactly! You put all the pieces of the puzzle together for the picture to fully emerge, not just the pretty flowers in the corner.
ae kusterer,
CI response rates may improve 100% or more since TILs are enlisted by DCVax in more than 50% of patients. This gives the CIs something to work with that many did not have before. Best wishes.
ae kusterer,
Maybe NWBO also feels strongly that M2 macrophages can be expected to be prevented from having a negative effect by just having enough activated DCs kept in the tumor environment long enough ( treatment spacing) with enough chemokine expression (DC selection and activation) to overwhelm tumor defenses and eliminate the tumor while at the same time building up immune memory cells (treatment duration) and creating a systemic response in up to 80 % of all solid tumor cancer types (maybe more with optimum selection and activation).
Sojourner55,
Glad to be here. What a story to tell and be a part of. There is drama, intrigue, investigations and tension from the quiet wait. Behind it all are a group of small companies, some research hospitals and 2 Lindas with a passion for helping patients and hoping to bring a major change to the way cancer is treated and perhaps cured. Thanks for your part here too. Best wishes.