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Jack2479,
As long as the eraser works at least you have a chance to correct mistakes. My eraser always works but it has been presumed upon way too much. Good thing it was given to me once for all (t)ime. Best wishes.
Pyrrhonian,
Good to see you post like you used to even though it's with a different point of view. Iron sharpens iron my friend. Best wishes.
Thanks Rkmatters. I saw but did not dig into that part of the agreement.
doingmybest,
I kind of read this the same as you but then there is the agreement Rkmatters pointed to that looks like it is for manufacturing. I need to go back and look at that again too so I have this straight. I did not spend much time on it originally as I somehow always expected manufacturing to be completely controlled by Cognate or affiliate.
hopefulsurgeonc,
I think UCLA and NWBO might be getting too caught up in the hope of a "We agree in principle" type of discussion. That carrot might be hanging from a stick on a string. Delays in written agreements are easy to manufacture but obtaining timely favorable financing not so much.
Turtle65,
I don't read greed as a major player into Linda's side and some big pharmas are overweight oncology so they could face dramatic financial issues themselves. Creative destruction is a difficult force to deal with. Linda wants change for the better and that starts with exposing the system and it's players. Best wishes.
doingmybest,
I hate to say this but the partnership idea seems to be a bit of a carrot on a stick to tease shareholders so they get upset if nothing happens soon while the company is in a financially vulnerable position. I don't expect Linda to give an inch to anyone that is not willing to recognize the full value of NWBO technology and patent chokehold. I don't even think VP Joe Biden will be able to break up this fight unless he sides with NWBO. I am sure Linda wants him to be on the side that changes the system that has hurt innovative small biotechs and perhaps may have hinted that he risks being exposed as being part of that system by default if he isn't. Big Pharma knows there will be a changing of the guard if they can not muscle their way into a leadership role in this discussion. That, in my opinion, is the whole point of the Moonshot program. To the general public this looks like a good faith effort to move research forward. To folks like me it looks like big pharma trying to put their pants on before the curtain goes up.
If there was a meeting between Linda and Mr. Biden without the big pharma liason then I expect she shared the NWBO experience and made something very clear to him. I bet she told him NWBO will go big or go home and big pharma is invited to join on legit terms or get moved out of the way. How dare she! LOL.
Be ready for scorched earth until later this year even if things are looking like news will come sooner. Linda is going to take this home with or without anyone else's help. Best wishes.
doingmybest,
Yes. Waiting for accrual (Dr. Prins) may also mean they are planning to add in the pseudo progressors. That would be "good news" not bad since they will only add them if the main cohort is good on its own. The "all patients appear to be living longer" means they may be preparing for this possibility. Manufacturing ramp up means they ARE preparing for this possibility. Best wishes.
doingmybest,
This is the canundrum:
1. PFS was the right endpoint for
seeking AA.
2. Because PFS was the primary,
FDA decided a crossover should
be required which would
confound the secondary
endpoint.
3. Secondary endpoints can be the
basis for approval in diseases
with limited options.
4. Will FDA take ALL evidence
into account including
analysis of post
crossover treatments and
use all available methods
to properly interpret the
data? Subject to sentiment.
5. The Phase 1/2 dosing regimen
was less agressive than
Phase 3 and the Dr. Prins
comments were not
directed at Phase 3 data.
6. Dr. Linda Liau's comment that
all patients appear to be
living longer was directed at
Phase 3 data.
7. Dr. Linda Liau's comment that
the required number of events
had not yet occurred also was
with regard to DCVax-L Phase 3
8. A rolling submission process
is possible based on Dr. Prins
comment about the Phase 3
trial still accruing patients
and recent suggestions about
manufacturing equivalency.
There may be a petition for a
patient rebalancing option
if needed or spot for
pseudo progressors to join the
main cohort which leaves the
new screening on hold pending
data review or other issues.
flipper44,
Thanks for sharing this shot of Dr. Coley.
flipper44,
Big pharma wants in on the feel good news so they can claim they slayed the dragon. Their guy has made the political connections through Joe Biden. Imagine what their PR departments can do with this. I would rather see Dr. Linda Liau and Drs. Prins, Bosch, Boynton and others with Nat Geo's Alan Butler as the "We beat cancer safely" promo.
doingmybest,
I know enough from research about what happens during activation and signaling to realize what I would try to do with the product at the right time for improved selection of activated DCs or perhaps even improving DC potency. This is one of several "light bulb turns on" moments I have had while doing basic research on cellular signaling and interactions. If there indeed is improved potency as suggested by the quotes referrenced recently on this blog, this might have first been caused by accident but I think NWBO and Cognate may have caught on quickly. Pure speculation but like I said, I know what I would have tried to do to tweak selection. I believe one of their patents actually gives a very nondescript hint by eliminating certain known activating agents for this process. Best wishes.
doingmybest,
What if, as I have come to believe possible from what I know about the equipment, process and NWBO's unique advanced understanding of DC maturation, there was an "unexpected" improvement in therapeutic outcome found in those who received treatment from the closed system process in the U.S.? Now suppose the Europeans first challenged then more recently approved it's use then indicated last week that they would accept the patent when the translations for final approval are accepted. Then on top of all of this the Europeans wanted proof of approved manufacturing capacity because they are extremely confident from what they have seen, ie expanded access, and their long history of DC research, that there will be high demand due to Doctor awareness and advocacy at large German hospitals.
This is purely speculative on my part but I believe the way Cognate improved selectivity of DCs from other cells with the closed system process actually creates a more potent DC and may have been done "accidently on purpose" to create a "suspicion is not proof of guilt" improvement. Kind of like using underinflated footballs in the playoffs. The time that has passed may just be the German process with a little frown added in from the "unexpected benefit" and nod of approval with the patent grant. This may be another part of the reason why all patients seem to be living longer and are creating the type of situation you have envisioned.
doingmybest,
If what you say is correct, even though NWBO left clues that manufacturing issues might likely be the reason for the temporary halt, then the next potential reason for the halt might be a rebalancing of mesenchymal subtype patients in the main arm due to pseudo progression and rapid progressor exclusion. Rebalancing would be for all subtypes if this is occurring and would be good science since a skewed patient population generally leads to skewed results. The company would need permission to have this done since the evidence tends to suggest that the 4 subgroups of GBM were not being individually accounted for in the original protocols.
Rapid enrollment can also be cause for a temporary screening halt. Regulators do not want skewed results caused by immature data so data is sometimes allowed to mature before screening for enrollment is allowed to continue. The rapid enrollment by the German hospitals may have caused this situation to occur.
"And let me add again, if management is so confident of the cards they're holding, then why are the warrants trading at $1."-Poor Man
That is simple to answer. Even if you leave out the possibility of stock price manipulation, those who have big money and are not funding at higher levels either can't buy or won't fund because their current situation dictates that they can't or is not prudent to do so. Institutional investors are net buyers as of 3-31-2016, though, so some big players are accumulating shares at these reduced prices. The rest either don't have confidence in their understanding of time frames, the science, regulatory situation, business model or other reasons. Those who do have confidence or are satisfied with their short gains are buying which is why there is a mini stalemate going on right now.
doingmybest,
The equivalency test that might be going on appears to be on a process that closes the system but also has resulted in an improved product with regard to quality and potency. This "inadvertent" improvement would need to be adjudicated as incidental would it not? Pyrrhonian, Bohsie and others had a very good discussion about this on SA a while ago when I mentioned that a manufacturing change might be the cause of increased DC potency. Best wishes.
Doktornolittle,
Still checking my notes with regard to your other request but just wanted to clarify here that manufacturing issues usually cause delays but are not always negative with regard to the longer term. Improved vaccine manufacturing is a positive that causes a temporary time loss cost to an investment. Best wishes.
Reefrad,
Linda said that they would continue to prepare for commercialization and that there might be some obstacles along the way. Rkmatters has very kindly taken the necessary time to show us what Linda Powers was hinting at when mentioning manufacturing issues being a major reason for partial or full clinical holds. As you have noted, NWBO's current situation, and clues given about it, pretty much is the foot that fits the shoe of Rkmatters' perspective. How long will the translations take for the finalized patent approval submission or might they already be done? Remember, one of the best friends of big business and worst enemies of cancer patients, small business and small investors is bureaucracy. Still, May is installation month. Tic Toc. Best wishes.
Rkmatters,
BINGO!!! As I said before to another poster, it's best to keep an eye on manufacturing developments. Commitment to manufacturing is how the Europeans weed out good prospects from poorer ones. FDA by itself will allow some flexibility with proof of potential to ramp up. With a multi continent strategy in place the stricter European requirements are being follwed.
Doktornolittle,
I am not a M.D. or a PHD. I simply have done some research into various immune cell relationships and non self antigens can cause DC responses that lead to improved migration. Intradermal injection places activated DCs in a lymph zone rich area. Lower dose reduces crowding not only of DCs interfering with DC migration but also from other responding immune cells like macrophages that kill unneeded or self antigen activated DCs which also contributes to crowding and leads to the death of non-self activated DCs because they can't get to a less crowded lymph zone interface before naturally coming to the end of their life cycle or being damaged from too much adverse signalling from what is happening around them. The lower doses helps prevent crowding and allows circulating T-cells to become activated in that local lymph zone. Recent research has shown that there are not only concentrated lymph zones throughout the body and tumor draining lymph zones but also lymph areas within at least some tumors as well. This is where DCVax-Direct can find an advantage.
DoGood DoWell,
I am guessing that NWBO might be addressing a need for; proof of production capacity ramp needed for European approval, manufacturing changes(upgrades) as per Rkmatters post(possible early trial vs later trial equivalency), possible ethicist intervention for mesenchymal/pseudos or at least rebalancing of patient subtypes if mesenchymal/ methlated mesenchymal population is under represented in the main cohort due to pseudo removal, an attempt to qualify and quantify potential patient benefit with UCLA biomarker test, probable gag order by legal counsel, and a potential FBI request to forego release of investigation results as long as possible so they can build their case(s) in a joint effort. Kind of like the FBI's Wall Street target version of the Manhatten Project.
Doktornolittle,
Hope I'm not out of place here but the lower dose, multiple site injection method is how NWBO sought to overcome this issue. The phagocytation of DCs with self antigen near the site of injection left small numbers of DCs to travel to the lymph zone. Good thing that various studies have shown that only small numbers are needed to activate a robust immune response. Eventually this response will be improved upon with isolated, tumor specific activated T-cell subsets that are the most active tumor killers and suppressors. Best wishes.
flipper44,
Seems to me that Temodar benefit will be tied to Tregs build and their needed depletion cycles in conjunction with immunotherapy as well as checkpoint inhibitor build and needed depletion to maximize CD8+ T-cell performance and development of memory T-cells.
TC Trader,
I wonder what Steppenwolf Speaks has to say about this "revelation" of institutional buyins as the price has dropped. Just rebalancing? LOL.
flipper44,
T and B memory cells should benefit from this regimen but CD4+ TREGS must also be accounted for. TREGS are depleted by Temodar so if CD8+ T-cell advantage can be achieved
and CD4+ T helper cells develop as a result then T memory cells will have a chance.
"Adam",
You guy(s) are too funny. You have yet to explain the importance of CXCR4 so here is another clue. CXCR4 is found on dendritic cells, a subset of T-cells and many types of cancer cells. What other imporrant PD-1 positive immune cells are they also found on? Once you figure that out then please tell me why NWBO ever bothered to develop a very expensive, fully automated grapefruit juice making machine that is probably being installed at Sawston and elsewhere this month under relative secrecy.
By the way, what is the true market value associated with the checkpoint inhibitor combination patent NWBO has based on known improved outcomes from checkpoint/DC combination trials? Is it somewhere between $1-$12.54 a share or more?
Evaluate,
Exactly. Damage control can take many forms. It's a multiple player chess/poker game. NWBO may have a knight penned in but still has their queen, rooks, bishops and a few of us pawns with positions making it difficult to get to the king.
Pyrrhonian,
I am not an expert either in production and development costs nut there are some on this board who claim to have some experience and the costs are said to be quite substantial. NWBO originally said it would take 2 years to develop full automation for Direct and who knows what else they are working on for L. There is a reason why most companies don't have production capacity until very near approval.
Pyrrhonian,
How much do you think a fully automated Direct process potentially installed at the Sawston facility this month would cost? Try working out the state of the art costs for that. Best wishes.
Turtle65,
Glad it helped you. Hope you Linda and Les get things patched up before the get together you mentioned a while back. I heard turtle number 65 wins his race against the hare and we can't have Linda and Les all upset about having to bring 100 bodyguards along when only 10 are needed to protect against big pharma and the hedgies. LOL. Best wishes.
md1225,
You are entirely welcome. These are just my thoughts based on market experience coupled with an attempt to logically take into account the historical time frames for regulatory decision activity, negotiation strategies, scientific evidence, manufacturing ramp up and what is at stake here. Best wishes.
afford567,
I understand your point well and agree that this could be possible. I also believe that there is enough integrity involved from who the investigators are to see one or more resign if they felt NWBO was trying to cover something up. My main point with agreeing with austinmediainc was that there are at least 2 investigations going on with regard to NWBO and one or both should have had something to report by now unless they were asked not to. Mr. Woodford would have reported on behalf of his investors and NWBO on behalf of theirs. This seems quite apparent. The fact that this has not happened in the face of deep losses over an extended period of time indicates that there may be something much bigger going on. The evidence continues to roll in that DC therapy and checkpoint inhibitors in combination hold great promise. NWBO's combination therapy patent, therefore, holds great value. The stakes at this point could not be too much higher since the Phase 3 trial has a planned ending in September and August marks the one year anniversary of the screening hold. This is an "all in" moment for both sides and that means winner takes all soon if an agreement is not announced soon. The agreement tease appears to be a backup plan for big pharma if NWBO can't be squeezed out before something big is announced. This creates the kind of tension we are currently witnessing. Keep September in your sights even if something should happen sooner. I believe this is the tension stretch period. Best wishes.
TiltMyBrain,
The goal, I believe, is overwhelming evidence with or without Martin's help. Then they show Martin his options, most of which do not include "Club Fed" or the witness protection program. I have a feeling a few legislators might be interested in their options as well since this all goes back to how the laws are written and who is taking advantage of whom. The FBI is still one place where some altruistic Americans reside. Best wishes.
austinmediainc,
Frustrated as we all might be to some degree or other, you are right about length of time needed to clear NWBO or refute Phase 5 report. Mr. Woodford is doing his own investigation as well so there are at least 2 potential sources of information from investigations. Should they both be taking this long? I don't think so but unraveling the connections between potential outside conspiritors probably would. NWBO is not the only biotech checking into price manipulation and the FBI is working on at least 3 major fraud cases right now, one of which will make Bernie Madoff's scheme look like child's play. I would not be surprised if the FBI is asking for all info being gathered from all sources with regard to this issue and asking investgating companies to remain silent while they build their case.
The recent supreme court decision that will allow individual states to hear company and investor complaints against manipulators is the first hint at what might be a big change coming in favor of the little guys.
Rkmatters,
I believe the B-cell activation of T-cells and or trafficking of antigens to the lymph zone for DC/T-cell interaction mentioned in your post may be something NWBO eventually talks about as well. Best wishes.
iwasadiver,
The key to regulating checkpoint pathways may all boil down to one very conserved and inescapable signaling molecular relationship which I believe NWBO understands very well. This is the reason their checkpoint combination patent will stand up over time and is a thorn in the side of big pharma and their investor advocates alike. Best wishes.
Doktornolittle,
I would really be excited to see an intratumoral checkpoint inhibitor/Direct combination trial even though Direct may be good enough on its own. The Phase 2 trials could be with either product or both but I'm leaning mainly towards DCVax-L only because more is publicly known about it and I believe comments made by Dr. Prins point to DCVax-L.
DCVax-L vaccine quantity is limited by tumor mass size and potential for unresected tumor being the location of additional key antigen targets. Production improvements have been made to maximize the number of vaccines made from resected tumor but if best dosing interval is much shorter than previously thought then even this additional vaccine may not be sufficient to reach optimum results. Checkpoint inhibitors should effectively act to stretch out the effectiveness over time of each vaccine. This should essentially allow enough time for residual tumor to be cleared from tumor cavities after resection as well as help prevent escape and possibly lead to immune memory with heightened immune surveillance imparted. Eventually UCLA plans to isolate key post DC vaccine activated T-cell subsets to be cloned to produce a DCVax adjuvant therapy. In the mean time CI combinations with DCVax should work fairly well to exceptionally well in most patients. Best wishes.
Doktornolittle,
This lymphocyte count correlation is significant not only for absolute count at screening but as it relates to longer term recovery to higher levels with time. NWBO wanted to make sure that those who could recover to higher levels were not having their results dragged down by those whose immune systems were being compromised because their lymphocyte count could not rise much over time even if their absolute count allowed them into the trial in the first place. As flipper44 said, SOC does not benefit from better lymphocyte count until they cross over so PFS benefit should correlate to prior lymphocyte count fairly well in the ITT population. Lymphocyte count may also correlate to the immunogenicity of the tumor type as well. Lymphocytes want to get to exposed tumor antigens and have the ability to access submerged antigens that will surface under the right conditions but are prevented from this activity because of improper activation due to cancer defense mechanisms. DCVax creates the right conditions for a short time with each vaccination. The improved dosing schedule, cell count and multiple injection sites will help.
Keep an eye on developments at Sawston. Just because NWBO may not be able to say much now does not mean we can't put expected time tables together. Three Phase 2s with rapid enrollment expected needs production ramped up and ready to go. I would imagine that best potential improvements (some may have been suggested by Dr. Linda Liau) will be built in as well. Best wishes.
Pyrrhonian,
Your analysis is indeed the normal course for small bios. In this situation, however, NWBO is sitting on news. They have news about commercialization preparation from Sawston, Memphis and Germany that is obviously tied to the regulators. If they are in the process of amending endpoints, this information could be released and according to those who see NWBO taking every chance to pump that they can, this update should have been publicly released already.
Steppenwolf Speaks,
You have been right about the stock price trend over the last 18 months as you stated so kudos there. This is an investment site so your perspective should be viewed as valuable since time has proven you correct. I have also said for a while that a scorched earth effort to drive this price down could well take place. Earlier this year I suggested news would probably come either in March-April or not until September. This view is based on historical active periods of regulatory agencies. The "Sell in May and go away" crowd has obviously made their presence felt in the recent weeks with NWBO as well so why the slow burn down from those who are negative on this stock instead of all out attack to force an earlier reverse split or bankruptcy possibility? Are they meeting resistance? We know NWBO will need cash again before September and that a reverse split could be held off until then based on a 180 day allowance to regain compliance once a price noncompliance letter is sent. This notice has not been given yet due the short period of time that has elapsed with the price under $1. With institutions accumulating more than selling, as I suggested might be happening and you countered thinking that this was not so, the evidence seems to point to a range bound cycle or even a rebound sometime in the next few months. I am sticking to the September or slightly sooner time frame due to the investigation report possibility and need for funding perhaps forcing the issue to some extent. What do you think?