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afford567,
It means somebody wants to buy or buy to cover cheap and doesn't pay commission doing it. They are mopping up the loose trader shares before they might need to pay much more. Big pharma definately has lips that whisper and Adam has been quiet lately but no matter what, investors should be prepared to wait for any news good or bad. Best wishes.
sentiment stocks,
Interesting that you should post this again. Did you happen to notice that Linda stepped hard on the brakes after question #1 regarding pseudos and rapids when she said the word "submit"? Submitting an abstract may not be the only place she was thinking of submitting data to as she said there might be something else "like" this done.
Rkmatters,
I think I am not connecting my points together well enough. Pseudos and rapids tend to be mesenchymal. If mesenchymal are also more responsive and risk being misdiagnosed as progressors then these patients are being kept out or moved out too early from the main arm which leaves mesenchymal type (most likely to respond) underrepresented in the main treatment arm. This would skew results so I believe some type of review of data might be requested to account for and or rebalance mesenchymal representation. If enough proof is given then this would not be an unreasonable request and FDA may be reviewing the data as it becomes available to verify the alleged concern.
Pyrrhonian,
Maybe I used the wrong wording. I don't think NWBO submitted a BLA but do think FDA and others want to see data as it accrues. I believe NWBO strategy is to have regulators be the ones who stop this trial or allow it to finish without intervention while NWBO is yet blinded.
By the way, if you hold your line steady for just a little bit you can detect whether or not you have a fish or a snag by the movement or lack thereof. I still have a fish. LOL.
Pyrrhonian,
I agree with you on this. To me it looks almost as if the company initiated the temporary hold, sent in data which FDA then reviewed and asked for continuing data as per Dr. Prins " still accruing patients" comment. This essentially leaves us with a rolling review of data up until the scheduled end of the trial unless there is or has been some sort of an ethicist intervention on behalf of pseudo/mesenchymal patients. If NWBO argues that these patients leave the main trial early and this leads to underrepresentation of this subgroup in the main arm, FDA might listen. Linda said they would not apply for AA until the end of the trial. To me this means FDA is actively trying to decipher data which is accruing very slowly while perhaps also working with the other regulator time lines and manufacturing prep so that approval can be expedited if received.
exwannabe,
Other than a feeling, what makes you skeptical of Direct's effectiveness when the optimized protocol is utilized? Do you understand how engineered T-cells are activated and how that might relate to Direct? Why do you think that Dr. Subbiah said that Direct could be at the forefront of treatment options for 10 years when he first saw it's potential? Why did automation for Direct find a way to jump ahead of automation for L as a NWBO priority? You are not alone in your skepticism. Then again most scientists let alone investors, professional or not, do not have the slightest idea why Direct's Phase 1 results were completely predictable even though better results were hoped for. There was an outside chance that the early part of the regimen would create a response long and strong enough to lead to overcoming immunosupression and create strong immune memory. What they have learned from Phase 1 will allow Phase 2 to create a dramatic difference in results since their hands were tied by "first in man" designation with Phase 1.
The immune system can be made tolerant or it can act very quickly and in some cases too quickly depending on how it is activated and supressed. NWBO knows this and is being careful to get it right and they are using the right cells to regulate response.
Steppenwolf Speaks,
Those who do not understand the amount of potential or the science needed to realize that potential rely on others for that understanding. The Motley Fool writers fall within that group as do most investors. If those who support the science give up on a mountain of potential too soon because of lost oportunity costs by those who fund them then that mountain gets left abandoned. A few miners always seem to find a way to hope for the unrealized potential of a premise that only time and effort have a chance to prove or disprove. This requires the right kind of inspired tenacity when the overwhelming sentiment is that what these remaining miners are doing is utter foolishness.
You are an investor/trader that looks at the technicals for investment clues in biotech and that works well for you. I look at the premise of the science behind company operations and the motivation of those who are driving it forward. Then I look to invest over time at or near cycle lows until that potential is proven or disproven.
Rkmatters,
In other words somebody thinks cellular products are going to be very important very soon. (:
Pyrrhonian,
Shark steaks taste good too. You just need to make sure you have some harpoons with you when you go after a big fish in shark infested waters like NWBO finally decided to do. Lol. I would be depressed about the shallowness of victories in life if all I had to prove their value was existance trying to prove itself to self. Hemingway seemed to struggle with this and expressed it in his work.
Just remember that it was big pharma studies that you posted on ihub that demonstrate the synergy between checkpoint inhibitors and DC vaccines. My fish is still on the line. Best wishes.
Pyrrhonian,
Maybe it's just fun trying to catch a 50# fish with 2# line or perhaps there is a more important message in all of this about who we are and the journey we are on together. Ever seen the movie "Gone Fishing" with Joe Pesci and Danny Glover? Best wishes.
flipper44,
You are right, I missed that one.
Steven has developed a habit of doing and saying things that can or are intended to upset those who do not agree with him but don't or can't explain why. He does at times want to learn more from the interactions but let's face it, true insights are often few and far between from any source. He likes messing with you Rkmatters and others because you do provide insights but senses emotions being provoked by his responses to you at times. This gives him a measure of satisfaction from being able to manipulate the environment which is what the deleted post is all about right?
Steven is just reflecting what is happening in the market. When big buyers are involved before news comes they drive the price down then load up. I told Steppenwolf Speaks that I suspected this was happening here and last quarter's numbers proved it. This is their MO and Steven knows this. Just like a politician, he likes to use what he knows to take credit for things that are beyond his control but others are willing to give him credit for. Missing information is just part of his game to see who is paying attention to the details. I think there is a better way for him to use his talents but even Jesus marveled at the servant who was fired but forgave much of the debt owed to his boss by others with the hope of landing a new job with one of them. Hey, we all make mistakes but there is nothing wrong with acknowledging those times when someone is right, at least temporarily. LOL. BE ST wishes.
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.