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You don't get it. They already did cover. They bought up tens of millions of shares in the last week. They own more of the company than most of the people on this board combined.
People who think that NWBO is going to squeeze the shorts or trap the manipulators are likely in for a disappointment. NWBO's goal is to get DC Vax approved and start making money. They do not have the time, money, or resources to go after anyone.
You really have no idea how shorting a stock works. Look at the price action today. In the morning it goes from $.67 up to about $0.71 or $0.72. There’s a lot of volume there as shorts accumulate shares for cheap. There’s a bunch of trading until 12:30 and then they walk the price down .2 cents at a time down to $0.65 then they start accumulating again.
Shorts have accumulated a couple of million shares today.
You are right that the shorts are walking it down. $0.0020 to $0.0040 a trade. Don't worry though, it will hold at $0.64.
Not sure which guys you are talking about.
Let me explain my perspective.
Clinicaltrials.gov should have been updated and the journal should have been released prior to any release of the topline data. Why? Because it would have provided some protection against short attacks on the data. I have explained this more than once over many months. You cannot release TLD (even partial TLD unofficially) and expect it to maintain share price unless the other things are done first.
Do I blame management for the share price dropping? No. I blame management for the share price not rising. Properly announcing TLD should have corresponded with a rise in share price because the data would show that approval is a formality.
Is the change to Clinicaltrials.gov a good thing? Yes. But at this exact moment in time it is largely irrelevant. I knew 19 months ago about the change. This is nice confirmation but is nothing special right now. It comes eight days late to have helped prevent or blunt Tuesday's blood bath. Is it a necessary predicate to the official release of TLD? Yes. But we don't know when that is, so whether the change came today or next week might be wholly irrelevant.
Was the information from NYAS good? Sure. But again, I had already come to the determination, as much as 4 years ago, that the data would be approvable. Some surprises, some confirmation, all good. But was it worth the company losing $1 Billion plus in equity? Not to me. The presentation was mediocre with the presenter not having seen a bunch of the slides before and spending most of the presentation saying everything was 'very very' exciting. I could certainly have waited another week or month for a full presentation of the data.
My issue is that for 19 months we have been waiting for TLD to arrive in a flurry of PRs, a journal, a conference, TLD itself, some write-ups in fancy publications and on the news. That all seemingly got thrown out the window and no explanation has been forthcoming as to why. Instead, silence. And rather than the stock heading toward some approximation of the company's true value, we are simmering away where the stock has been for the last 6 months.
Given how this was handled, it makes one question how the official release will be handled. NWBO does NOT have a history of competent communications. I still think DC Vax will be approved, become the new SOC, be worth at least double digits, make me a lot of money. I would just prefer to be moving on that road now rather than waiting who knows how long for approvals to start rolling in.
Other people are entitled to their own opinion. I understand people being excited about the results or the updated website because it IS confirmation, or maybe news they did not expect. It just wasn't worth the price to me. I get that ultimately none of this is likely to matter in the end but I have short-term needs that this is hampering and any delay costs me a lot of money as prices and interest rates rise.
Correct, the information on clinicaltrials.gov is only really relevant to arguments that the trial failed because PFS failed. That ship has already pulled a 'Vasa.' It is important that it is updated prior to any journal article being released or the official release of TLD, whenever those event might occur. Otherwise, it is simply a useful confirmation for people here who already knew about it in October 2020.
Flipper, yes NWBO requested the change (according to sentiment_stocks) but since then I have seen at least two posts about contacting the clinicaltrials.gov admins about expediting the change. It just feels like people are on a vigilante tear.
I must say I find this disturbing.
It is not the role, in my mind, of investors to expedite updates to clinicaltrials.gov or correct reporting of the company's data. If people actually believe that management has some kind of plan, then it is the company's job to deal with these sorts of things that their planning has caused.
They deliberately (for reasons as yet undisclosed) refrained from having the clinicaltrials.gov website updated more than a year-and-a-half ago when the other websites were updated. In addition, they deliberately declined to publicize the change to the other websites. It would seem that they have some sort of plan and without knowing what that plan is it seems unwise to go messing with whatever timetable they are working under.
Making threats and accusations against people reporting negatively about the data is not appropriate. In addition, no one here speaks on my behalf much less on behalf of the company. I think that people will have a lot more success explaining why something is incorrect than making threats and accusations but if people feel like that is the right path, please make clear that you are speaking solely on your own behalf and not as some spokesperson for those of us who have not authorized you to act on our behalf.
The mere suggestion that TLD was going to be announced got the stock to almost $2. If the journal and TLD won't move the stock, then why not release TLD in October 2020 as originally promised? Rollout of journal and TLD need to be accompanied by other PRs and news stories explaining the finding. You don't need to be a doctor to know that a cure for cancer (the literal Holy Grail of medicine) is a huge thing and if properly publicized, will send the stock skyward.
When you have no idea what you are talking about, best to be quiet. No one has to prove that something wasn't a short attack. He is innocent until proven guilty. YOU are making unproven accusations on a public form that someone committed criminal offenses. THAT is defamation, specifically Libel.
In order to prove that AF or others defamed NWBO or participated in some collusion to illegally manipulate the shares of their stock, you need to prove that they intentionally published false information, knowing it to be false. Statement 1: clinicaltrials.gov shows the primary endpoint of the trial is PFS. Statement 2: company claims PFS failed. Where is the false statement? "Well the company also said they updated the endpoints." So what? Presented with conflicting statements by the company, it is perfectly reasonable to go with the official government website, especially as the company has had 19 months to update it if the endpoint were changed.
By failing to update the clinicaltrials.gov website, NWBO allowed AF and others to make factual statements that cast doubt on the results of the Phase III trial. AF did not have to lie. What he did elsewhere is irrelevant to what happened here. If AF and others are bad actors, then it seems that putting in just a tiny bit of effort to mute his attacks would be effort well spent.
Prove it was a criminal short attack. It is fine to make allegations but the simple fact is that NWBO left AF and others with a wide open door to make legitimate attacks. If clinicaltrials.gov is not updated, then there is no official evidence of changed endpoints and if PFS is the primary endpoint, then the trial failed. Even if the trial could still succeed with the original endpoints, pointing out that the trial appears to have failed based on information supplied and updated by the company (clinicaltrials.gov) isn't illegal, immoral or unethical.
As I said yesterday (https://investorshub.advfn.com/boards/read_msg.aspx?message_id=168870579):
There is no requirement anymore for news to present both sides to a story (that was the Fairness Doctrine). Most stories have an angle and they report the facts supporting that angle. If the piece is about how the company is a fraud, because they 'hid the results' for 19 months, the test failed, etc. then they will report the facts in the worst possible light to the company and only those facts that fit the narrative.
While pseudo-progression might explain the failure of PFS, if that is still the primary endpoint, then the trial failed. Why would they talk about the external controls if that isn't an actual endpoint of the trial? Until the company updates clinicaltrials.gov, people can reasonably claim the endpoints have not changed.
To be clear, I am not saying they are right, I am not saying that what they say is true, I am not saying they don't actually know the truth. My point is that they can make facially valid arguments without obviously acting in bad faith as long as the website is not updated and no journal article explains the results in detail.
Not at all. Companies lie and exaggerate findings all the time. But it is reasonable to assume that if a company says something that is against their self interest, then it is probably true (that is why there is an exception to the rules on hearsay for these kinds of statements) and it has long been believed that the trial failed PFS because of pseudo-progression. The presentation was just confirmation.
However, the claim that the endpoints have been changed is directly contradicted by clinicaltrials.gov, something the company is supposed to have control over. Given conflicting information, why would you not accept the official version on clinicaltrials.gov?
I get it, we know better (or believe we do). The point is, there was an easy fix for this and the company didn't make it. Maybe there are reasons why but they aren't talking. In the meantime, shorts can continue to hammer this point until the clinicaltrials.gov website is updated. Just because shorting is inevitable doesn't mean you need to make it easy on them.
I look at this from a legal perspective. If you want to prosecute someone for a crime, you need to be able to prove every element beyond a reasonable doubt. One of those elements is the mens rea or intent. That might require that you intentionally, knowingly, negligently, or purposefully did something. Proving someone's mental state is difficult but sometimes their actions give them away.
An example is a drug courier. If you were driving to a restaurant with a friend and they stopped across the street from a UPS store and asked if you could run in and pick up a package for them because they were in a No Parking zone, you probably wouldn't think anything of it. However, if someone you barely knew offered you $50 if you would drive with them to a UPS store and you would go in and get a package and then return to the car, you would think that there was probably something illegal in that package for them to offer you a bunch of money for something they could easily do themselves for free.
In our case, the clinicaltrials.gov website, which is believed to be updateable by the company, states that the primary endpoint of the trial is PFS. If the company is claiming the endpoint is changed, then why haven't they changed it in the 19 months since the trial ended because you can't change it after data-lock? So it is reasonable for shorts to claim that the endpoints have not changed. Likewise, the fact that cross-over patients seem to do better than DC Vax-L patients requires some additional explanation. Hence why they need to have a journal article.
So yeah, maybe if they had done everything right, this all still would have fallen apart but then there would have been actual evidence of malicious intent and bad faith. Instead we are in a squishy grey area that no one is likely to touch. When the Washington Post piece came out several years back, other news organizations came to AF's defense. Without actual evidence of a crime, suggesting a journalist committed a crime is not a good move.
Sorry, thought that was implied. The thing is, AF is not involved in good journalism and never has been. He is in the business of trashing companies based on vaguely-plausible arguments. The company made no effort to get good journalists to provide timely information, and they did not present the findings officially, doctors did. It is hard to make the 'shorts are evil' argument to regulators and journalists if you provide the shorts with plausible (if false) arguments. It is something that the average investor can check, the clinicaltrials.gov website (which the company can apparently update) clearly has PF as the primary endpoint and it is correctly reported that PFS failed. Time to sell.
Bad faith requires more than 'he should have done more research.' AF is under no obligation to accept the company's word on what they will do. It is perfectly reasonable for him to use the clinicaltrials.gov website as an official statement by the company if they control its contents. If they can change it now, then perhaps they should have changed it before the presentation. My point is not that AF's arguments are valid, my point is that at least some are facially valid and that makes it really hard to show bad faith.
If it is up there soon, then great. But if the timing is based on a statement from the company, especially an off-the-record one, then I would not bet good money on it turning out that way.
The point might eventually be moot but at the time of the talk it wasn't, which is likely a large part of why the company lost $1 Billion in value and why it will be difficult to pin the whole episode on a calculated campaign by shorts, which is the point of the initial post.
All that said, I think it is great that you support the company, I do to. But all indications right now are that they screwed up massively with this presentation. While there may be explanations, I want to hear them before I vote for share authorizations, directors, and other matters. If the explanation is 'we screwed up,' then that is fine as long as there is some remediation plan. If there is no explanation or some lame blame shifting? Not so good.
Yes, the presentation made by an outside doctor said that. However, the endpoints have NOT been changed on the official website that is supposedly controlled by the company and the company has not publicly stated when or if they will be changed much less why it hasn't been changed yet. So the current verifiable information is that the trial failed its primary endpoint in the US. The company appears to have the ability to make correct this but has declined to do so, thus creating a perfect argument for short sellers.
For 19 months we have been under the illusion that the holdup was journal publication that would prevent the sort of bloodbath we witnessed last week. The process is a simple one. Drop a couple of PRs so that people outside of the medical community and this board have heard of NWBO. Update endpoints on clinicaltrials.gov. Publish journal article giving in-depth analysis of trial results. Have articles/shows ready in major news outlets. Release TLD. Present findings at major conference. Announce A, B, C. <--- Flaskworks, BLA submissions, patents, whatever. Instead, they went with 'have doctors present partial findings in semi-private venue, hope for best.' Maybe there is some reason for this but we have no idea what it might be.
I have no doubt shorts are responsible nor that they have consistently battered this stock over the last decade. However, knowing of this history, putting zero effort into defending yourself, and setting things up to fail is not IMO a great strategy. Maybe there is an explanation but we have not heard it, so we can only guess.
I think sentiment_stocks suggested that the company was making the change but it would take a month (not sure if I read/remember that correctly), and if that is the case, they are going to continue to have a real credibility issue through ASCO.
Some advice on soliciting investigations of short sellers
If you want someone to investigate and publish stories about/prosecute short sellers, then provide some actual evidence. Who manipulated the stock? How did they do it? Is this a pattern? What other stocks have they manipulated? Who can corroborate this?
First, ideas are a dime-a-dozen. Coming up with the idea for a story is not all that difficult. Creating that story is the difficult part. Professionals have lots of story ideas but it is the actual investigation and writing of the story that requires time and effort. If you had written a dozen books and a fan came up and said "you should write a book about pigs in space!" your reaction would probably be, "you should write a book about pigs in space if it is such a great idea."
Same is true for prosecuting crimes. As a federal prosecutor I did not lack for cases. Nor did the various law enforcement agencies with which I worked. They routinely refused to investigate cases that did not meet various thresholds (like loss amount) or because there was not sufficient evidence or witnesses with which to make a case in court.
Second, stating that results were good but the stock went down is a conclusory argument. There is no provided link between the price going down and the good news. In the legal profession, the term res ipsa loquitur (the thing speaks for itself) is used in liability cases in which a defendant is in control of a process and the result of the process caused damages but the plaintiff does not have the exact details as to why or how. However, the stock market is not a closed process over which a single group or individual has complete control. There are many factors and players at work.
Several possible explanations for the drop on Tuesday have been forwarded, including swing trading, short selling, panic, and stop-losses. Not all of these are necessarily illegal or nefarious. Swing traders are groups who coordinate buying and selling in order to achieve short-term (days) profits. They do not necessarily know anything about the companies they trade in but get tips on stocks that are ready to move. While such groups can be used to manipulate stocks, they are not necessarily nefarious. There is evidence to suggest that they were used to boost NWBO stock running up to Tuesday.
One of the primary arguments made by short sellers on Tuesday was that the trial failed its primary endpoint. This is a 100% true statement given the available evidence. The primary endpoint from the trial is still listed as PFS, even 19 months after data-lock. There has been no official confirmation from the company that the endpoint was changed. The presentation clearly shows PFS failed, as has long been suspected. Without any direct information from the company, a presentation showing that you failed your primary endpoint is not likely to help your stock price.
Without a journal article or at the very least a statement from the company in advance, the stock was bound for a deep dive and first-hand accounts suggest that the company knew that going in. Why they allowed that to happen, why they decided to release partial data in a semi-private venue, why they have not updated clinicaltrials.gov, etc. are open questions.
None of this it to say that the stock is not manipulated. I am not suggesting that short sellers were not partially, largely, or wholly responsible for the selloff on Tuesday. There have been plenty of clear examples of short manipulation of NWBO over the years. But if you want an article written or a prosecution undertaken, then do as much as you can to provide actual evidence, witnesses, methods, or other information to the recipient. Because personally, I would bet most people would rather do a story on Tesla's loss of $300 Billion in market cap in 6 weeks and what impact Bill Gates shorting the stock had, then what happened to a tiny biotech stock no one has ever heard of before.
ILT:
I have no problem with things going badly. I have no problem with the fact that there are people out there trying to destroy NWBO. I accept that, always have. That is part of the risk of any small biotech. Maybe if they had put out a journal article, bought some Super Bowl spots, had some nice write-ups in trade mags, national newspapers, a few talk show spots, and a big speech at ASCO, they still would have gotten crushed. But at least they would have put up a bit of effort.
They did nothing. Instead of waiting for the article ('set to come out very, very soon'), which was supposedly why we have been sitting here for 18 months without news, they dribble the news at a semi-private gathering in the middle of a trading day when the stock is still trading with no hint of their side of the story.
Perhaps they wanted to shine a spotlight on Linda Liau, great, except that she didn't even make it there. Maybe they wanted to catch the shorts, stupid but whatever. Maybe they needed to get some info out in order to push publication of the new end-points. OK. Maybe they wanted to put on a show for Big Pharma in order to get funding for combo trials or partnerships, great. Maybe, maybe, maybe. Whatever the case, they have until the ASM to explain why they did (or didn't do) what they did and why it was worth $1 Billion in shareholder equity, especially when they apparently knew the short attack was coming.
Ike
Except that they have not officially released TLD. If they officially released TLD properly, then we would not be in this mess.
EDIT: Here are the terms from the 8-K:
Diver,
I very much appreciate your perspective, thanks for the first-hand info. I am not, however, feeling any better as a result.
We have been waiting for more than 19 months since data-lock for top-line data. For myself, it has been more like 5 years, since expectations of data-lock and trial results at ASCO 2017. I am fine with having continued the trial for three more years to get the survival tail data. I am fine with waiting 19, or 20, months for analysis, external consultants to find the right external controls, for manufacturing to mature, for some certifications, and for publication in a peer-reviewed journal. All of those things are going to help with approval and help boost share price post release of TLD.
However, if the journal is in fact coming 'very, very soon,' then there was no reason to 'leak' a preview now. I would far rather wait a couple of weeks or a month and get a well planned event that puts the share price through the roof than the fiasco we just had. I didn't need confirmation that DC Vax-L works, I have known that for four years. Yeah, nice to have more details, nice to have some of the additional data. None of it matters. I have said many times that share price does not matter until TLD. Well it matters now and it @(*^$.
What makes anyone think the share price is going to come back in the near term? It was sitting between $0.60 and $0.90 for the last 6 months. It only increased above $1 because of signals that TLD was coming. People need to stop saying that the shorts are done now. They are not. They do NOT care. They are going to hammer this stock and hammer the data non-stop because they have been doing it for years and it works. They don't care if their arguments have been debunked. They don't care if the people in the know don't buy their arguments. They have limitless resources to push their narrative and every time NWBO screws up like this week, or when announcing 'data-lock in a month' at the 2020 ASM, or announcing 'results by the end of the month' in September 2020, NWBO's credibility gets flushed down the drain. If NWBO cannot come up with and execute a plan to release the data and significantly increase share price, then they need to be replaced with someone who can. I still think they have done a great job getting us to this point but without the discipline to see this through, they become a liability going forward.
NWBO has about 1 month to get share price permanently over $4 and get moving on relisting the stock on an actual exchange. No more share authorizations. If they need more shares, there are 150MM+ the Board can give back when needed. You know what is painful? Waiting 5 years for an event and then watching NWBO share-holders get fleeced out of $1 Billion in equity in one day for ABSOLUTELY NO REASON. THAT is painful.
Ike
He has been shooting his wad for 10 years and gives no indication of slowing down or stopping. Enough people still listen to him to get his drivel stickied on this board. And now NWBO just handed him all of their ammunition.
People don't care so much about science that they don't understand and none of this is straight-forward and simple, hence waiting 20 months from Data-lock to share TLD. I 100% guarantee that we will hear the 'Common Sense' argument. "They post-hoc changed the endpoints, knowing the trial failed, and when they released the data to the public on May 10, the market reacted to the obvious failure. Common sense tells us that if the data was so good and the treatment worked, the stock would be at $100 right now and the end-points would be updated on the Clinical Trial site . . . "
The journal article and a PR blitz were supposed to insulate us from the negative spin but now in addition to overcoming that, they also need to explain why the stock tanked and has not recovered after X days/weeks. Not to mention that the shorts have time and details they did not previously have in order to come up with any little thing to cast doubt on the results. Take it from a former prosecutor, the way the defense attacks a case is by picking up the little inconsistencies that exist in everything. The more time and information they have, the more little chinks they find in the armor. The more time they have to test their attacks to see what works, the more pernicious they will be.
I don't disagree, that seems the most likely reason for arranging things the way they did. And Linda Liau getting sick was unanticipated and put them in a tough spot. The question is, if shining a spotlight on Linda Liau was the reason they agreed to something suboptimal, why go through with it when that wasn't even going to happen?
Maybe they didn't want the blowback from the shorts, the conference, the BP execs, or whatever, but we have no way to know because we are hearing nothing. I was perfectly willing to give them wide latitude if they were holding things up for a journal in order to avoid exactly what just happened but as of right now that is not the case and if they want support they need to earn it back.
Waiting an indefinite quiet period prior to approval is not a reasonable request for management to make at this point. If there is some plan, it better show up quickly.
Cancelling would have been bad but at least they would still have TLD to announce on their own terms. We are back where we were before the 2-3 week run-up prior to NYAS. That run-up was mostly in anticipation of the conference and with a muddled picture the price is back where it was as if nothing ever happened. That is not a good thing given the strength of results.
I do not know exactly what happened on Tuesday but I suspect, as has been put forward, that it was a combination of factors, including swing traders who are just in a stock for short-term gains, as well as some people still having stop-loss triggers for some reason. I have no doubt that people shorting the stock contributed but they could easily have covered 10s of millions of shorted shares during the panic.
The thing is, as long as we are on the OTC, we are far more open to manipulation, few if any institutional investors will touch the stock, and the general public is far less likely to be able/willing to buy. Getting the share price over $4/5 should be the MAIN focus of the TLD announcement so that they can uplist and be ready on an actual exchange when approvals start rolling in.
Getting to $4-5 now is going to be far more difficult because the shorts now know exactly what the company is going to say, has time to prepare and test counter arguments, and can pretend that the market already reacted to the trial's failure (even though we know that is not what happened).
It is. The point is that it needs to be out before you tell everyone about TLD so that you don't get slaughtered and can defend yourself. THAT is why you wait 18 months.
sentiment_stocks:
I agree that the presented numbers are good, certainly enough for approval. Not sure that the mOS on newly diagnosed is quite what people were hoping for but the recurrent numbers are excellent. Given the lack of toxicity, approval is a no-brainer.
The presentation also puts to rest the reason for the enrollment halt and shows that waiting on the long-tail probably saved this trial from failure. It also suggests why waiting for 18 months for a journal article in a peer-reviewed journal made sense and why they likely switched course back in 2020.
However, they blew their chance to control the narrative and they can't just have a do-over. The data is out. Presenting TLD 'officially' is a big nothing-burger now. You can see the people on this board talking about 'the market knows' and that is the perfect shorty comeback to whatever NWBO tries to sell now. "Yeah, they announced TLD a month ago and the stock lost 70% in value because X, Y, Z and everyone knows it." There was momentum going into Tuesday that is now lost. Worse, now those lining up to keep NWBO down have a look at TLD and the time to plot out and play-test their arguments.
What was the point of not releasing the data 18 months ago if they were just going to release at a paid-for event most people have never heard of in the middle of the day with no follow-up? The only way this even makes sense is if the journal article is coming out this week and the non-disclosure rules made this the only way forward. Even then, I doubt they can recover the momentum and share price. They need a PR blitz to end all PR blitzes in order to get the world to really see what we have here.
Come July, they are going to need money and that requires increasing authorized shares. If the stock isn't trading in the high single digits to low double digits by June, don't expect a lot of enthusiasm by investors for further dilution. The stock should be at $5+ right now.
Waiting for TLD until the share price rises is one thing, waiting on approval is something quite different. I have never cared that much about the share price but having my first 7-figure day be a negative one is not at all how I envisioned the release of TLD. Now that TLD is out, they don't get the benefit of the doubt anymore when news and results are not forthcoming.
DC Vax-L Phase III Trial Top Line Data
Slides: https://virtualtrials.org/dcvax/dcvax.pdf
Video: https://www.youtube.com/watch?v=wYh4Ec7ByLQ
Transcript:
Tuesday May 10, 2022 @ 11:10 EDT
Frontiers in Cancer Immunotherapy
New York Academy of Science
Dr. Paul Mulholland (University College Hospital)
(Thanks Linda Liau, notes she was supposed to give presentation but is unwell.)
I can tell you its my absolute privilege to share this data with you. I hope you find it as exciting as I think of it. So, I am going to be today presenting the final results from the DC Vax-L Phase III trial and discuss with you the innovative trial design and also share the results. What do we know about Glioblastoma? I just want to set the scene really, because I think that without setting the scene people might not really appreciate the exciting data, the landmark data that I am about to share with you.
Glioblastoma is a very aggressive primary brain cancer. It hasn’t, so far, responded well to immune therapy. It’s classed as being immunologically cold. Its a very difficult tumor when you look at it genetically it’s extremely heterogeneous and then very very able to change and evolve and evade treatments. It’s got a very invasive phenotype and the recurrence rate is approaching 100 percent if not 100 percent. It’s universally fatal, really.
The Standard of Care is to have surgery and its not possible to take all the tumor out. Due to the Glioblastoma being such an invasive tumor, there are always cells left behind and there’s always recurrence, unfortunately. However, the more tumor that’s removed, the better it is for the patient’s survival. So following surgery, in standard of care, there’s six weeks of radiotherapy, that’s Monday to Friday on the brain, five days a week, thirty treatments, along with chemotherapy. And then, six weeks of more chemotherapy.
It really is quite a grueling, punishing schedule of treatment to have all that radiotherapy and chemotherapy. However, it does not give them so much survival advantage. So even with all of that treatment, the average survival is around fifteen to seventeen months. Tumor recurrence occurs within the first year and then the median overall survival from recurrence is six to ten months. When you look at what we might call long-term survivors, which we classify as five years in Glioblastoma, that’s actually only five percent.
So it really is a very difficult disease. Then the question is well what’s been done about it? Well, there has been a lot of clinical trials in this area. There’s been, if you look at this publication, from 2016, 2018 sorry, there are 417 clinical trials for Glioblastoma and this included nearly 32,000 patients. Of all of those trials, including 16 very big, expensive phase III trials, only one showed evidence of efficacy and that was the tumor treating fields device. Since then there’s been more failure in Glioblastoma.
So it really has been a real battleground filled with lots and lots of failure. When we look at the actual treatment itself, the treatment originally was surgery and radiotherapy. In 2005, it was shown that from a large phase III study that by the addition of chemotherapy (Temozolomide) there was an addition of 2.5 months. This actually was really groundbreaking at the time because it showed that actually chemotherapy could make a difference to Glioblastoma. We were very hopeful at this time that actually we could then improve outcomes. But to date, we have not.
There has been no real change, aside from this, in the last 17 years. There were, there was some data from Gliadel wafers, and these are chemotherapy that are put in with the, during the surgery. They’re not generally used. They don’t have much efficacy and they’re not very popular to use.
I’m pleased to tell you that we’ve, I’m going to share with you the results of the dendritic cell DC Vax phase III trial. When we look at the trial itself, what happened for these patients was that 331 patients, from 94 trials sites, from four countries were recruited. The patients were all patients with newly diagnosed Glioblastoma. The patients had surgery and then the tumor tissue was taken and sent off to the laboratory. Following this, the patients had leukopheresis. With this, they were able to manufacture dendritic cell vaccination therapy.
The trial was a double-blind, randomized trial and importantly, it had crossover. The trial began a long time ago now, back in 2007. Enrollment was suspended between 2008 and 2011 and the reason for the suspension was nothing to do with safety or any other reasons, it was actually purely for financial reasons. Fortunately, the trial was opened up again it was, investigators were very enthusiastic to be part of the trial. From 2012 to 2015, 92% of the patients were enrolled in this study. With the last patient being enrolled in November 2015.
With this trial it’s been important to wait for the long-term survival data so we can see what effect the immunotherapy has over a long period because it’s actually with immunotherapy we’re looking for what it does to that proportion of patients and their long-term survival.
So this shows the screening and enrollment. [slide] It was actually a very straightforward study for us to treat patients. The patients were screened, they were enrolled, they had their surgery, the tumor tissue was taken, it was sent off to the laboratory, and then the leukophresis was done three weeks after the surgery. Whilst the patient was undergoing chemoradiotherapy there was manufacturing of the dendritic cell therapy. Then, when this was completed, the patients then had the autologous dendritic cell vaccination, just as an intradermal injection into the arm. Treatment was given alongside the standard Temozolomide chemotherapy. Depending on how much vaccination they was able to make and patients had treatment at day zero, day ten, day twenty, months two, four, eight, and twelve, and then every six months thereafter. I have to say from my experience, the treatment was extraordinarily well tolerated and I saw no side effects in any of my patients.
The trial was a crossover design. The reason for this was because at the time it was not considered ethical for patients to undergo leukopherosis, which is invasive, and then not have the opportunity to have the vaccine at some point. It was extremely important that this was included, but this did create difficulty later on and also opportunity later on.
Therefore, the original primary endpoint when the trial was designed was progression-free survival. At this time, when I think back to then, we weren’t really aware of this concept of pseudo-progression. Pseudo-progression is something that we see and we recognize very clearly now. It occurs with immunotherapy but it also occurs when patients have radiotherapy and Temozolomide chemotherapy. So what happens here is that patients have the treatment and then if you do a scan at the end of treatment it looks like the tumor’s grown. In fact, what you’re seeing is swelling , and dead tissue, and tumor infiltrites with lymphocytes. Actually, they’re a response to treatment and these patients generally do better when they have pseudo-progression.
Therefore, at this time we didn’t have good imaging to differentiate tumor progression from pseudo-progression, which we do now. That’s why the progression-free survival needed to be removed as the primary outcome measure. In fact, this is the results [slide] from the progression-free survival. Which isn’t very surprising. So when you look at progression-free survival and there was no significant difference between the two patient groups.
However, when we look at overall survival, which is obviously what’s most important, this was made the primary endpoint in the study and included in the statistical analysis plan prior to the unblinding of the data. When we look at the SAP [slide] we see that the primary endpoint was overall survival in the newly diagnosed Glioblastoma patients. What they’ve done is they’ve looked at external controls for this study because 90% of the patients in this study ended up receiving the vaccine. Which, you’ll see, is actually very important for the patients with this recurring disease. I’m very please that they were had the opportunity to have the vaccine.
So 232 patients of the 331 patients had the standard treatment plus the vaccine at newly diagnosed. However, at crossover, 64 patients had recurrent disease and also then had the vaccine, So we have the data for the survival for the newly diagnosed and the recurrent patients. This then means that we need external controls for the newly diagnosed and the recurrent patients.
The external controls needed to be sourced and validated and needed to be done independently of the sponsor. An independent expert firm was appointed to evaluate other Glioblastoma patients that were treated in clinical trials. They were given a criterion to match very closely with the patients in this particular study. I’m just going to show you very briefly how the validation was done [slide] but not discussing in detail.
When we look at the external controls [slide] we can see that these are very well known and very accepted publications that we used for the external controls for the newly diagnosed Glioblastoma patients and also [slide] the external controls for the recurrent patients. You can see how well these patients are matched. This data will be available later for people to scrutinize but I’ll just show it very briefly. [slide][slide]
Now we’ve come to the most interesting part of the talk, which is actually the study results. I’m very, very happy to say that the primary, the median overall survival in newly diagnosed Glioblastoma patients reached statistical significance, as did the secondary endpoint, that is that patients with the recurrent disease who had dendritic cell therapy had improved survival. The safety profile was excellent. There was 2193 doses of DC Vax administered. Only five adverse effects were reported and no significant immune reactions.
The important landmarks are that the median overall survival for patients with newly diagnosed Glioblastoma was 19.3 months from randomization and 22.4 months from surgery. This is versus 16.5 months that you would expect normally and was seen in the randomized controls. The methylation of MGMT, which is a good prognostic marker for these patients, showed a very enhanced survival of 30.2 from randomization versus the normally expected 21.3 months. What was extremely impressive is that the survival at five years in these patients is 13% versus 5.7%
When we look at the recurrent Glioblastoma, the median overall survival was extremely impressive as showing a 13.2 months median overall survival, as opposed to the 7.8 expected overall survival. Even here, we see a survival tail. At 24 months we see 20% of patients alive at 30 months 11%, which is much better than you would expect for these patients.
There’s been innovation in this trial and this had to come about because of the crossover design that was required in this. But this is the first phase III trial of a systemic treatment in 17 years to show significant extension of median overall survival in newly diagnosed Glioblastoma. And the first phase III trial of any treatment in 27 years to show a significant extension of median overall survival in recurrent Glioblastoma. These are extremely important statements and are very very exciting and really important for this patient group.
What is particularly important is that this phase III trial shows meaningful increases in long-term survival both in newly diagnosed and recurrent Glioblastoma. What’s interesting with this particular treatment is it has no, little or no, toxicity. It really is suitable for combination with a wide range of other treatments, which people can spend a lot of time thinking about checkpoint inhibitors, oncolytic viruses, cytokines, chemotherapy, etc. What’s really also very exciting is with this particular technology is that when the patient recurs, and they have further surgery, you can make a new batch of this treatment. So the target, so this tumor evades treatments because it changes, but you can actually just change the treatment with the tumor. Potentially, this works in Glioblastoma, so actually it can actually work in other tumor types. It’s really a very very exciting technology.
This slide [slide] just looks at how it can be combined and what people can do with it in the future. So this [slide] shows the overall survival curve in the newly diagnosed patients and you can see this is very, very favorable and you can see very clearly the, that’s there’s no crossover and you can see the long-term survival, which is very impressive for this group of patients. So these [slide] are the important landmark survival rates in the newly diagnosed patients. At 36 months, you have 20% survival, 48 months 15%, and 60 months, five years, over 13% survival as opposed to what you would expect normally of around 5%.
When we look at the subgroup analysis [slide] you can see here that actually in every subgroup analysis there’s a favorable outcome. When you look at age and residual disease and when you look at this particular marker which is MGMT, that when it’s methylated, the patients have a favorable outcome. You can see it’s much more favorable when they have this treatment.
This is looking at newly diagnosed Glioblastoma [slide] and this morning this is the first time that I’ve seen this slide and I’m really very, very intrigued and very excited that this shows that this technology, which is extraordinarily well-tolerated, is showing an increase in survival in patients over 65. And, you’re showing long-term survival in this patient group. When we look at the under-65s, these people have a better prognosis generally but actually, with this technology it’s actually improved further.
Then, when you look at this [slide] very poor prognostic factor of significant residual disease, this is really impressive. You’re seeing that this technology, this dendritic cell therapy, is impacting on this patient group in a way that I would not have predicted, so it’s really very, very interesting. When you look at the patients with minimal residual disease [slide], there’s always, there’s also an advantage in survival there.
This is the methylated groups of, this is people with the favorable gene configuration of methylated promoter region of MGMT [slide]. When you look at the five-year survival in this group, it starts to look really interesting. Really, there is nothing that could have predicted this survival in this patient group. It’s so impressive. This is the patients who’ve got a very poor prognostic marker of unmethylated promoting region of MGMT [slide] but even they have a survival advantage, even though it’s smaller.
Then we come to the recurrent Glioblastoma, where really very little makes an impact. I would not have anticipated that these patients would have had an impact with dendritic cell therapy. But actually, when we look at the overall survival in recurrent Glioblastoma, you can see the survival and if you treat this condition, you’ll see that that is a very favorable survival curve for recurring Glioblastoma. We’re seeing 13.2 months median overall survival and we’re seeing a tail, a survival tail that goes out to five years.
Here we can see the landmark data [slide]. In recurrent Glioblastoma, six months is a landmark because people aren’t expected to make it six months. With dendritic cell DC Vax-L, their survival is 90% and at 24 months, 20% survival. Which is really very very impressive. At 30 months, we’re seeing 11% survival.
Dendritic cell therapy, how does it work? I think that this audience is probably more familiar with that than a brain tumor audience. It uses the master cells of the immune system, the dendritic cells, to mobilize multiple elements within the immune system. The technology that’s used in manufacture of DC Vax-L is fully personalized. It inherently targets antigens, which are actually on the patient’s tumor, and fits the patient’s version of the cancer. It really is a personalized vaccine. Unlike other technologies, it uses all of the tumor antigens, not just some manufactured peptides. It makes, and this makes it difficult for tumors to mutate around the antigens that have been targeted.
This just shows [slide] a slide on how the dendritic, autologous dendritic cells work, and how they multiply and activate these T-cells. This is just a slide [slide], there’s actually a lot of evidence that the T-cells cross the blood-brain barrier, both in animal models and also now in humans. This is some unpublished data from Linda Liau, which shows infiltration of T-cells into Glioblastoma tumors that were treated with DC Vax-L.
In conclusion, this [slide] is showing the completion of a large, phase III trial including 331 patients. It was really a mammoth effort over many years and I was very very honored to be part of that journey with all my co-investigators and with Northwest Bio. There was 94 sites, 70 clinical investigators, four countries. I think it’s very exciting that we’re seeing practice-changing results. Not only in newly diagnosed Glioblastoma, but also in recurrent Glioblastoma.
I can say from personal experience that this vaccine is easily administered and it has a very very favorable side-effect profile. The use of these external, contemporaneous clinical trials is innovative. I think it’s been really important for this particular trial because the patients in this study who had recurrence had the vaccine and the vaccine was effective that actually we need these external controls. What’s particularly significant is that there is a significant percentage of long-term survivors. That’s consistent with immune membrane effect by the T-cells. This really can change the natural history of Glioblastoma. I don’t think we’ve seen that with any other treatment.
We’re still looking at the data on this and I’ve only seen some of this data this morning and I’m really quite overwhelmed by it. That we’re seeing sub-populations that I wouldn’t have anticipated to see benefit, or seeing old patients, patients with residual disease, doing really well with this treatment, which is really quite dramatic.
So this treatment is really feasible. Because there’s no side-effect profile, or very little side-effect profile, it really is possible for this to be rolled out as a treatment around the world. Thinking about how we can use it going forward, of course we need to think about combination treatments and we also need to think about what is this, how is this changing the immune micro environment. More work is ongoing in that and I think it is a very exciting area of research.
So in summary [slide], patients with, treated with DC Vax-L showed a clinically meaningful and statistically significant extension of survival in both newly diagnosed and recurrent Glioblastoma. Patients have an excellent safety profile and it’s really noteworthy to see these long tails of survival.
I’d like to thank Linda Liau for giving me the opportunity to speak today, sorry she was unwell to miss the talk and I know that will be a regret for her and also to Dr. Robert Prins, who led the study from UCLA and to my colleague Professor Ashkan at King’s College and to all my colleagues who are investigators and sub-investigators and the Trial Steering Committee and of course to all patients and their families who participated in this landmark study.
End: 11:30 EDT.
Note: I removed lots of 'um,' 'and,' and 'so' as well as general stutters. Where relevant, I noted where he was referring to slides. I transcribed everything by hand, with some help from the YouTube close-captions.
So you expect them to drop a PR in the middle of a trading day?
I simply said that without a journal article to back it up, TLD will not hold share price up. I am a little lost as to the announcement strategy so far. Not at all how I think I would handle things but I don't know what they are allowed to say and what they are not, nor what is coming.
There will be another presentation in June
To everyone saying they should have released TLD 18 months ago:
They announce statistically significant results and the stock bombs from $1.90 to $0.69.
Yeah, releasing TLD will boost the stock price.
mOS: 19.3 mos from randomization
22.4 mos from surgery
13% survival at 5 years vs. 5.7%
Primary and Secondary endpoints statistically significant.
Only 5 significant events.
Suspension 2008-2011 for financial reasons.
Who cares?
He has never said anything worth reading.
Gary:
We are going to see John Mulaney later in the year! His last special talked a bit about the intervention, which was the first I had heard of it.
I expect to be watching Linda Liau's presentation online. Will try to get a transcript out if I do. I would be a bit surprised if the presentation comes without any prior announcement or news if this is an actual release. Guess we'll see.
Ike
Thanks! The waiting . . . how it drains one's soul. Fortunate for me that I am a lawyer and long ago dispensed with mine. 3:-{>
Someone needs a hug.
Sorry I can only provide a virtual one. <Hug>