Stock of Interest (NWBO): Potentially Lose $0.5 or Gain $30 or More in Near Future

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  • Annual Shareholder Meeting 2018 notes taken by a share holder IkeEsq:
    NWBO 2018 Annual Shareholders Meeting
    February 2, 2019 at 13:30 EST
    1050 Connecticut Ave, NW, Washington D.C.

    In the room: Linda Powers (LP), Cofer Black (CB), Les Goldman (LG), Jerry Jasinowski (JJ), Marnix Bosch (MB), and Dr. Navid Malik (NM)
    On the phone: Alan Boynton (AB) and Lisa Porter (Computer Share the transfer agent)
    Approximately 30 share-holders in attendance

    Total shares outstanding: 519,729,780
    Total shares represented: 460,778,896 (Ike note: someone coughed during the 800 which could be off the rest of the numbers are good)
    88.6% of shares are present, meaning there is a quorum

    Three proposals, no shareholder nominated Directors, all three proposals passed

    13:45: Formal Meeting adjourned, informal Q&A begins

    (Ike note: Questions are paraphrased, answers in quotes are verbatim quotes, speaker initials in parenthesis)

    Question 1: One of the attendees asked why there was no response to her letter to the company in reference to increasing the share price sent in January 2018?

    Answer (LP): Unaware of letter, copy presented, LG/LP will respond. (Ike note: It appears based on the conversation that the letter was an offer to provide expertise in raising the stock price based on the attendee’s previous experience as a VP in charge of raising the stock price for a Fortune 500 company) “We would love to have dedicated people and when we get bigger we will certainly look forward to having that.”

    Question 2: What is the status of combination trials?

    Answer (LP): “I can talk about what we’ve said publicly.. . . What we’ve said publicly is a couple of things. First off, we feel that our technology is very well suited for a lot of combinations. Combinations with checkpoint inhibitors, combinations with targeted agents, it’s really well suited for combinations because of the mechanism of action of how our technology works and because the safety profile is so utterly benign. You know, if you’ve seen other combination trials for example of two checkpoint inhibitors together, the toxicity of that is so high that there’s a 40% dropout rate from the patients just because of the side effects, right? So we are very much looking forward to doing combination trails. There has been public disclosure about two combination trials that we would like to do with DC Vax-L for example. One that we announced publicly was a . . . and its still there on the table for us to go forward with when we are ready . . . it’s a combination trail with DC Vax-L and Keytruda, the checkpoint inhibitor drug of Merck. That trial, which we did announce publicly and has been approved by Merck, and those agreements were signed and all that, but as small as we are we haven’t yet been able to launch that trial in parallel with everything else. But that should be a very interesting trials when we do it. Colo-rectal cancer is the number two cancer, second only to lung cancer. And if you’ve noticed in a lot of the publicity about immune-therapies, there’s been surprisingly little attention to colon cancer. If you also notice in the literature, checkpoint inhibitors, which are the big darlings of the pharma industry right now, have had no effect, none at all, in any patients with colo-rectal cancer except patients who have what’s called MSI, microsatellite instability a particular version of colon cancer, which only 5% of colon patients have. So we think that’s going to be a very interesting combination trial and we are looking forward to the day when we have enough resources and we can go forward with it. The other combination trial that we have said publicly, and actually it wasn’t us that really said it publicly, it was UCLA that said it publicly, is a combination trial together with BMS’s checkpoint inhibitor in brain cancer, and that would be for recurrent brain cancer. Gioblastoma. Our current trial, as you probably remember, phase III trial is for newly diagnosed Gioblastoma. Just to finish on that, that’s the beauty of, in our view, of the DC Vax-L and DC Vax-Direct technologies, they’re platform technologies. We believe, forward-looking statement, will be applicable to any type of solid-tumor cancer. So those are probably the two most tangible ones, those are the ones we talked about publicly. For us it’s a resource and bandwidth issue. Both of them are there to proceed when we have the resources and bandwidth to be able to proceed.”

    Question 3: Will NWBO unblind data prior to ASCO?

    Answer (LP): "ASCO is certainly a great venue and it's been great for us when the timing has worked out, to be able to, as we did last year we had just announced the first interim data from our phase III trial, three days before ASCO, that just happened to work out beautifully on the timing. And a few years before that we had unveiled our initial DC Vax-Direct data. So we agree with you that it's great when that works. I can't answer your specific question about what is going to be the exact timing of unblinding. What I can tell you is what we said in our press release on November 19th, which was right after the SNO conference and right after that we had announced the updated data from the clinical trial. And we said, here are the steps we have to go through in order to get to unblinding and then what we would do with the unblinded data. And you can look at what those stages are and you can read what we said that each of those stages is a multi-month process. And so you can figure the arithmetic. The first stage, as we said, we have to get the Statistical Analysis Plan developed and then submit it to regulators, and approved by regulators. That doesn't sound like much but it is a ginormous exercise. We are working with teams of experts. Neurosurgeons, neuro-oncologists, radiologists, regulatory advisors, statisticians. All of these advisors in a big team, which is the right way to do it, and there's a lot of complexity, to say the least, about the statistical analysis plan and the statistics that you put in. There's no one way to do it. If you read all the literature, and there's no single cookie-cutter 'this is how you analyze a dataset from a phase III trial, bum, bum, bum.' There's a lot of decisions and choices to be made and stitched together into a coherent plan. You can perhaps understand from the description I just gave you, which I don't think rises to material by itself, description of what goes into the process, why we say that each stages is a multi-month process. Because you go through that process with two-dozen experts, and then you go through the process again in regulatory approval of that statistical analysis plan. And remember, we're in four separate countries with four separate regulators. Which, yes, it is more complex and takes longer, but also means we have multiple chances to win. So it's worth, and we believe very strongly it's worth the extra effort and expense and time and so forth. So I know it's really frustrating.

    In parallel, and yes, people ask us all the time, 'are you at least doing things in parallel when you can?' Yes, we are. That thought has occurred to us. What we're doing in parallel is doing the final data collection. We had 82 sites in four countries with three languages. In order to do the final data collection a CRA Clinical Research Associate, employed by the independent CRO, the organization who is managing the trial independently, has to physically go to the sites, sit down with the trial database and the hospital records and compare them and find any piece of data that's missing or there's a discrepancy. The way the data gets captured in a clinical trial is in what's called a case report form. A case report form can be a hundred pages long. And you're looking for any piece of data that's either missing or there's a discrepancy. At every one of these 82 sites for every one of these 331 patients. And each one where there's a piece of data missing of there's a discrepancy, generates a query. And a query has to be resolved and the resolution has to be validated. The process can involve thousands of queries. That's just normal. That's what it takes to close out a dataset. And get to the point where we have a clean, full dataset that we can go to data-lock on.

    So the big things that we are working toward and which we are doing in parallel, are moving toward the statistical analysis plan getting done and approved by regulators and moving towards data-lock. I hope that my description can help you see when we say it's a multi-month process, just making the physical visits at 82 sites and then resolving the thousands of queries you can understand why that's a multi-month process. So that's what we're in the middle of and we're as anxious as you are to see the results. That's the best I can tell you of the steps and the timeline."

    Question 4: Can you provide a roadmap to your marketing plan to increase stock price, who will be the focus: patients, hospitals, stock-holders, etc.? (Ike note: Turned into a question about Right-to-try)

    Answer (LP): That's a very interesting question, we were so hopeful about Right-to-try because so many patients that really want to get access to the treatment and as a company as tiny as we are we try to do as much as we can in terms of compassionate use patients and Right-to-try. Unfortunately, it turned out that the legislation was passed with restrictions in it that made it unworkable. The reason I say that is because as tiny a company as we are, we don't have the resources to be able to absorb the cost and provide it for free or partially free for patients. We need the patients to pay for it. And the Right-to-try was thought to usher in a new regime where that would be possible. Unfortunately it turned out that clever lobbyists for those who were not in favor of that legislation slipped in a cross-reference and the cross-reference within the legislation said that basically it says that basically you couldn't do any charging of patients any more or different than under existing rules. Which negated the whole thing. And so, we had to give up on that, so we're not doing that, which is the answer. So what we are focused on now is getting to the finish line with the trial and everything related to the trial as vigorously as we can."

    (LG): "I might just add, in terms of your bigger question, which is 'do you have a plan to get a better value in the market for what the potential is,' I think that was your question, and the answer is while the Right-to-try will be litigated, because it is actually an interpretations of some of the provisions, it's not going to help anybody who's got GBM or any other solid-tumor cancer right now, so as Linda said, that's not available to us now, some other countries have a more liberal approach. The answer is 'yes' and you are beginning to see the mosaic of some of those things, like the release we put out a week ago, I don't know if everybody's seen it, it takes the data we've already got and puts it in perspective with regard to the fact that solid-tumor cancers do not seem amenable to being dealt with at all by the Big Pharma immuno-therapies, which tend to be single-targeted. Some of the data in that release is rather stunning, talks about how many failed GBM trials there have been ever since [??] was approved. It's strengthening our internal ability with regard to outreach to investor relations, in terms of media and getting more attention as the data gets more and more serious more hospitals are talking about it. But these things don't happen right away and even with regards to the opponents we have, that spread misleading information. We do have a total campaign but one of the things we need to do is to stage it in a way, whether it's at ASCO or before or after or what have you, that the timing can come to a crescendo of sorts and not stick little pieces out there that then just get shot in again. And we've learned that lesson from the past and we're working at strengthening all those areas and getting continuing information out just like we got out a week ago yesterday. And I think you'll be seeing more and more of it and I think we're better off not laying it all out at once because then the other side will have more to attack us on. Producing those results, strengthening those capabilities of our little company, I think will be the key to eventually getting the market to pay attention."

    Question 5: Can NWBO ovecome all of the forces that are aligned against them?

    Answer (LG): "We're still here. Lots of people didn't think we would be."

    (LP) "I can only give a couple of comments from a personal perspective. Everyone in this company is committed in a deeply personal way to this company and this technology, for whatever their respective, personal reasons are. Nobody would go through this degree of abuse for this long a period of time for a business, and certainly not to collect a salary paycheck, as is regularly suggested on the message boards. I personally think that if we could get through what we've gone through the last three years, I kind of think we can get through anything. The year 2015, we had come out . . . we had just made very strong presentations, I believe many parties were surprised, at AACR, the largest research conference in the world, and ASCO, the largest clinical conference in the world. We were hit with multiple class-action lawsuits, we were hit with the anonymous Internet report, we were hit with an attempted hostile takeover. We were hit with just incredible things. When we look back on it now, it's just amazing. In 2016 and 2017, were pretty horrific in their own way. And I've must say, this team, everything we do we do as a team. We do everything by unanimity. Management and the board, we have just kept doggedly putting one foot in front of the other. And we do say to ourselves not infrequently, 'well, we're not dead yet.' And we take satisfaction in the fact that somewhere there's a conference room with the bad guys in it who are saying to themselves, 'what does it take to kill these people?' Because what's been thrown at us, stock manipulation, you name it, is staggering. But, this team will never give up. We might be crushed like a bug but we will never give up. And at this point, with the dataset . . . I hope everyone can appreciate the year 2018. The year 2018, at least in my perspective, was really transformative for us. We came out with two sets of interim data from the clinical trial. It's not the final data, it's not unblinded. The future may look different. That's a classic forward-looking statement. But that interim data was . . . and I am only allowed to say really conservative things . . . that was encouraging. No one has ever seen that kind of survival in GBM with any agent or combination of agents. 'That doesn't mean the future will be the same as it has been.' I mean, that was transformative. The financial deal we did in December was transformative. I'm told that one of the bad guy commentators now says the only thing we've ever been good at is real estate. At least we are good at something. With that dataset and the commitment of this team, all I can tell you is I believe that if anyone can get through this, I think we have as good a chance as anybody to get through what we are up against."

    (LG): "I only have one other thought, which I give a lot of thought to actually. In the context of your point about 'with the better our stuff gets the tougher and meaner the other guys get,' there's another word that goes with tougher and meaner and it's more brazen. And the more brazen they get, maybe they're walking into a trap. That's as far as I'm going to go, because they have been . . . we have to be conservative in what we say . . . we'll use the word 'outlandish' in how brazen they've been and the better our stuff gets, the more obvious they're going to have to get and at some point, if you have built the right things that I was talking about before, with investor relations and media and you're getting the story out there about the little engine who could, there will become a tipping point, I sincerely believe, that they'll do themselves in. And we want to be there to catch it, and that's all I'll say about it but it isn't just a one-way street where they rule the world, it gets tougher and tougher the better we get and that provides angles we can work with."

    Question #6 If the forces against you are so strong, why not partner with someone?

    Answer (LP): "So that's a question that's come up in each of the last several years and it's usually related to a pharma partnering. Pharma partnerings are done all across the spectrum and we've now seen the first couple of major acquisitions and partnerings with cell-therapies. Most recently, as of about two years ago, you didn't have pharma . . . dealing with a living cell product requires an entirely different manufacturing facility, an entirely different supply chain and distribution chain. And big pharma didn't have any of that. So they didn't have anything to bring to the table except a checkbook. They didn't have any operational muscle to contribute. I think that is beginning to change. And as we said last year, if we were to get the proverbial 'offer you can't refuse,' we wouldn't refuse. I asked last year and I'll ask all of you right now, at our current stock price, and our current company valuation on the one hand and with what's in the company, would you want us to do a partnering at this stage?" (Response: It depends on the deal. Not a buyout but perhaps a partnership or giving up a certain market.)

    (LP) "There are various ways to slice it, one possibility for example is one could do regional partnering deals. That would be quite sensible. No reason that's not possible. One of the great things about our intellectual property and our large patent portfolio, we file them everywhere. Even in far-flung locations. And when we did that we wanted to have something that would be useful in various regional settings. So that kind of thing, I think, is a practical possibility. I'm not making any comment other than to say that it is a practical possibility."

    (JJ) "Let me just add to what Linda said, I've done a lot of other mergers and acquisitions myself in other areas, you really don't want to do it unless you are on some ascendancy, you don't want to do it. And I think we are close to that point but we're not there. And you don't want to do it when the stock price is low. Your point's a good point but you have to look at it in the context of evolving further and our stock price rising. On that point, Linda, I just wanted to add to what you and Les just said. As a director, I honestly believe we are in better shape now than we've been for several years. The results that Linda mentioned are really quite unusually good. Secondly, we have now financing which we didn't have before. It's not a small thing, when you're paying a bit at a time. And I think our team has actually strengthened a little bit, particularly on the investment strategy side. I think we're going to be telling our story better in the next three-to-four months. For all of those reasons, I have to say that I am more optimistic about the company than I've been for several years."

    (LP) "Let me finish the other point that I wanted to add, in agreement with all of Jerry's points, the tricky thing for us when we think about partnering is that each of our two products is a platform technology. Most of the other companies that you see that do early- or mid-stage-partnering, have a number of discrete products. And they'll partner Product A and keep Product B. For us, it's the same product. Yes, you could do a licensing deal or a partnering deal for a field of use, but in terms of being able to police that and really get the corresponding value, it's pretty tricky when it's not separate products. So that adds to our feeling of making sure we don't do something premature."

    (LG) "In addition to the stock price and the timing of what to do, I think that the biggest meanest players, they have 100s of billions of dollars in their revenue stream related to the basics of chemo and radiation. If we take a step back and use conservative words, their effectiveness in terms of the response rate is much worse than ours, they cost a lot more to make if you're looking in the immuno-therapy area, and they're much harder to administer, much more toxic, I mean we're really kinda good in that area, and of the hundreds and hundreds of billions a large chunk is just the money they make from the drugs that ameliorate the effectiveness of the painful stuff. So if you take a step back, they don't mind picking up another, which is the subject of what we said a week ago yesterday, another targeted immune therapy. But we cover all solid-tumor cancers. Potentially. That's what we're working on and that's what they would be buying. But the point is, they would be eating their own revenue streams. And they have to think twice if it isn't a combo-trial where they are enhancing something, if it's a head-to-head competition that's a daunting proposition for them and they are not going to be anxious to speed up the day when their stuff is a little bit more obsolete. And that's a big consideration when you're dealing with the biggest guys."

    (NM) "The checkpoint inhibitors have been the darlings of the immune therapy space. It's very important that they been successful because prior to their success, immune therapies space was being held back by a lack of data. The checkpoint inhibitors have delivered spectacular revenue growth, and they've been pounding the table doing trials and combination trials. But what has been challenging is that big pharma companies that are behind checkpoint inhibitors are effectively working with antibodies. That's their bread and butter. So they're trying to get the antibody products to work in a way which will deliver greater revenue than their pricing commensurate with that. However, what we're starting to see with the checkpoint inhibitors, there's a number of trials going on, and the interesting thing in the UK, [] is that the checkpoint inhibitors, other than the low-response rate that we talked about, we're also starting to see that weaknesses of the checkpoint inhibitors. They're being thrown at cancers they're still single [unintelligible] and we're starting to see in some of the trials patients that are progressing rapidly rather than benefiting from checkpoint inhibitors. And I think what will happen is that the whole immune therapy space is going to start to evolve into a more balanced, into a more biological . . . "(Ike note: he got into details I didn't understand and between his accent and the distance from me, I can't tell exactly what he was saying. Summary: it is biology and not mechanism that will drive immuno-therapy and big pharma is focused on mechanism)

    (LP) "I think that's an important point. Our perspective is that the field is moving in our direction. And the field is moving in our direction in several ways. We feel like the field is moving in our direction partly in what we covered in our press release last week and my presentation at Phacilitate, is starting to realize that solid tumors constitute the vast majority of the market, 80% of all cancers. And even checkpoint inhibitors are making very limited inroads on solid tumors. And the T-cells aren't anywhere yet. The concept that a silver-bullet agent and a silver-bullet target are not going to stop a highly-complex, heterogeneous solid tumor. That concept is beginning to really start to register in the field. And that's one way in which the field is moving toward us. And another way, what Navid touched on, actually you were too kind to the checkpoint inhibitors, it's not just the patients are progressing rapidly in spite of taking the checkpoint inhibitors, their beginning to discover a phenomenon called hyper-progression. In which it looks like the checkpoint inhibitors are gasoline on the fire. And they don't know right now what's causing that or which patients, what bio-markers, what profiles. So, increasingly, if you're a patient thinking about taking a check-point inhibitor, or you're a doctor, you might be helped, you might get hyper-progression, gasoline on the fire, or you might have no response. So there's this whole dawning realization that checkpoint inhibitors are definitely not the answer to everything. And indeed, with this phenomenon of hyper-progression, which, by-the-way people are having difficulty getting their papers published about this, is anyone surprised about that? Is another in which the field is moving in our direction. The further we go, the other thing that is really important, I wanted to say about our data, we've received tremendous abuse from bloggers and whatnot about taking too long with our phase III trial. But one of the ways the field is also moving in our direction, is realizing how important it is to have long-term data and get to see the far tail of the survival curve. We were subjected to excruciating pressure to go to data-lock and finish the trial. Long before the data we reported last November. That data was presented in a plenary session at the Society for Neuro-Oncology, the biggest meeting of Neuro-Oncology subjects in the world. That's a big deal. Again, it's interim data, it's going the future could be different. But just toughing it out, and getting data without the long-term tail of the curve, and I know it's been very hard for shareholders, it's been frustrating, it takes a long time, it's like having to wait on Christmas morning, I want to tear into my presents. But that was so valuable. If we had succumbed to the pressure and gone to data-lock sooner, neither we nor the rest of the world would even have known what was possible. What the capability . . . I can't attribute causation . . . but I can say that no one would have known that patients who received DC Vax would have such longevity. Some of this, we just really have to tough it out and we're so grateful for the shareholders who grit their teeth and tough it out with us."

    Question #7 Have you engaged any external financial advisors to discuss valuation of the company and when do you plan to get off of the OTC?

    Answer (LP): "We have informal advisors that we talk to, that Les talks to, on a regular basis. But in more of an organized effort, that's something that lies ahead of us. We are now in a position, I think, to be able to have those of discussions in a much more effective way because of the developments during 2018. With the data and the money in the bank we're able to have much more productive discussions. So that's really something that lies ahead of us based on what has just been achieved in 2018. The second question I can't answer."

    Question 8: Where are the shares coming from that are use to short NWBO's stock?

    Answer (LP): "Those are great questions, I'm so glad you brought that up. I'll tell you where they'ee getting the stock from, they're getting it from all of you guys. And that's something we are painfully aware of and thinking about and that's all I'll say right now. Most people, most retail investors don't know, that when you sign up for an account with a broker, they usually steer you into a margin account even though most people aren't buying and selling stocks on margin. You're not taking debt to magnify your investment. Buried in these 100-page contracts, you know when you go and click accept, we've printed them out, these 100-page contracts, and buried in the middle of them, the broker can lend out your shares, that you bought, and you own, they can lend them out and there's only one use to can lend them out for, there aren't multiple uses and we're not sure which one they're lending them out for, there's only one use for lending shares and it's to lend them to shorts. They lend them to shorts, they receive stock loan fees as revenue to the broker for lending out your shares, and they're not required to tell you they are lending it out, they're not required to tell you the money they receive, and the only usage of lending out your shares is to drive down the value of your shares. That is the state of affairs today with brokers. And it's even worse when the brokers will put you on this OBO list where you're not even, it's not even visible that you're the shareholder. The best thing is if the shares are in your name, not the street name, not the broker's name and you don't want to be on an OBO list and you don't want to have a margin account, but a lot of the brokers make it difficult or impossible or adverse to have a different type of account. [] The best thing that you guys can do to help, is spread the word far and wide on the message boards, tell everybody, have your stock in your name, do everything possible to be in an account that is not a margin account, unfortunately from what we understand, the rules are being bent, quite far, so that even when it's not supposed to be lendable it is being lent [] at least if your shares are electronic, this really matters. Because in our company estimates are that staggering amounts, in the triple-digit millions, can be involved in this and if we have about 14,400 shareholders, and if everybody would get their shares out of this situation where the brokers are lending itm out without your knowledge, and getting paid handsomely by the shorts for doing so, and keeping that revenue, and by the way, there's lawsuits between the big boys over the amount of loan fees being paid, that's how big the money flows are coming from this. And if you have your shares in an IRA, that's the most juicy target for these brokers because you're not trading. They just sit here. And the more they just sit there the easier it is for the brokers to use them and do this. So the best thing that you guys can do to help, which would be an enormous help, is spread the word and get all the fellow shareholders to get their shares out of this situation. And dry up the supply of shares for shorting Northwest's stock."

    (LG) "Let me just add one thing, we're always thinking about this. As part of my answer before, there will be programs and they will involve numerous activities. But we don't roll them out one-at-a-time, it'll be part of a total package." (LP) "We can't talk about that."

    (Attendee discussion with broker who claimed NWBO is not shortable because it is a penny-stock)

    (LP) "Your broker either genuinely believes that and is mistaken or they're lying to you because that's factually wrong. [] Start by putting . . . having the stock in your own name and putting it in an account that's not a margin account. Those two steps, which you'll probably get hassled about putting it in a non-margin account, but those two steps, in your own name in an account that's not margin, already is a big improvement. [] Before we leave this, let me just tell you, in the process of collecting the votes for this meeting, we had large-share owners, to the tune of many, many millions, even tens of millions of shares whose shares were missing. And the broker couldn't explain it. And we spent days and days going up and down the chain, and helping the shareholder find and get their hands on their shares. As many as 10, 15 and more millions of shares at a crack. That's the scale of what's being done here."

    Question 9: Is the deal with Huawei strictly a real estate deal or is there possible future collaboration? Concern about IP theft.

    Answer (LP): "Right now the Huawei deal is just the Huawei deal, it's just real estate. I don't have any reason at this moment to think it's going to be more or different than that. In terms of the physical setup we sold most of the site. We retained 17 acres, of ownership, we also retained the very large, roughly 90,000 sqft, facility, which is ginormous, for a clean-room manufacturing facility of cellular products. Retained that. And a very large amount of space around it, I think the lease is filed with our SEC documents so I'm OK to say this, things like 600 surface parking spots, surface parking spots, specified. You can't put us in a multi-story car park. Large amount of [space?] for plant and equipment, the plant and equipment of air handling and wire handling is ginormous. It's physically separated, there's physical berms, there's chainlink fence with barbed wire on the top that surrounds it. It looks a bit like a prison but it's OK. Huawei is not allowed to set foot in our facility, they don't under the lease they don't even have the usual landlord rights to enter into the premises, it's highly restricted, and the only time that they can come in is if they have signed a confidentiality agreement and they're escorted. And even then, it's further restricted that they only see what's in compliance in our determination with our regulatory requirements and that includes controlled access to the building. There's a lot of things built in that I think give us pretty much everything that you can humanly have for protection. We are physically separated, they can't enter our space and so forth. I think it's not impossible that if Huawei doesn't collapse from everything that's going on, would we ever consider a regional partnering in China? No reason not to consider it. But there's nothing contemplated right now."

    (LG) "To give you further confidence, the documents themselves, have very clear language that says we will not be competing with them, i.e. we're not going into the telecommunications business, and they won't be competing with us, they're not going to be in the medicine business."

    Question #10: Is there ongoing dialog with the FDA regarding formation of the SAP and will you wait to unblind until after the SAP is approved?

    Answer (LP): "Definitely 'yes' we won't unblind until the Statistical Analysis Plan has been approved by all regulators. FDA and other, four regulators. We intend publicly as a company policy, which is pretty standard for companies, we don't talk about our communications that are ongoing with FDA or other regulators. We only say results, so I can't comment on interim communication type things, but in case there is any [lack of] clarity about remarks earlier about the SAP, it is an actual submission to the regulators. Like when you apply for an IND, that's Initial New Drug, application to get a clinical trial approved or when you apply to get a new product approved. You make an actual submission to get your SAP reviewed and approved."

    Question #11: Does new infusion of capital help speed the process?

    Answer (LP): "Working with the huge team of experts that we're working with, we have several of each, it's like Noah's ark, we have several statisticians, we have several radiologists, we're kind of maxed out, we're not limiting the SAP process by funds, by money, at the moment. We've got top experts, by the way who are completely independent, they had no involvement in the trial, they weren't involved in signing it or executing it, or reviewing it or anything. There isn't more that we can throw money at that will make it bigger or go faster. We're already 'pedal to the metal.'

    Final comments (JJ): "If you look at the numbers on the votes associated with what we handled today, you're really staggered by the extent to which there's a lot of shareholder support for the company, for the directors, for Linda, etc. And I know that that extends in large measure to many of the people around the table and I just wanted to personally thank those of you [] for coming for the meeting and we will try to do better and better about responding but we really value our shareholder base. It turns out that Northwest Bio has lasted this long in addition to Linda and Les's leadership, because of the support of retail shareholders. And that's you and I want to thank you personally."

    (AB) "The only thing I would add, is we have been at this, I have for 25 years and we will never give up until this is available to all brain cancer patients, and that will happen."

    Meeting closed @ ~14:40.
    IkeEsq Sunday, 02/03/19 01:24:29 PM
    Re: None
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    Post # of 212343
     

    GlobeCitizen

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    Northwest Biotherapeutics’ Annual Shareholder Meeting Key Takeaways
    Wednesday, February 6, 2019 at 9:13AM
    Michael Bigger
    Feb 6th 2019, $NWBO, $0.24, $128M market capitalization

    Carlo Rago, PhD

    The well-attended Annual Shareholder Meeting (ASM) on Feb 2nd 2019 strengthened my conviction for NWBO. All of the board’s recommendations were approved and there was a sizable turn-out in person or proxy. While I believe that the initiation of analyst coverage could immediately help NWBO realize a more appropriate value as a Phase III clinical asset in the hot immuno-oncology space, the key takeaways from the ASM are focused on fundamental value:

    1. The company is laser-focused on the series of steps that they identified to get to top-line data, which will be the major value-inflection point.
    2. I have extreme confidence in their ability to execute the steps
    3. I get the sense that they have enough capital to execute the steps, particularly with the remaining 17 acres in the UK that can be monetized, if needed.
    4. The steps are each multi-month processes and there is some overlap where there can be parallel processing. I'm guessing this means 6 months of work, but we are 2-3 months into the work, so I'm guessing top-line data could be available at the end of May. Notably, ASCO is May 31st - June 4th - The company is compelled to unveil at ASCO because it is the main event for revealing clinical oncology advances. On the other hand, some have guessed top-line data will be available at the end of the year. February 12th is the deadline to retain the opportunity to submit an abstract to ASCO 2019.
    5. They have stated that they are submitting the Statistical Analysis Plan to four distinct geographical/market regions - This gives them four independent chances at regulatory success and four chances at commercialization/revenue. i.e. the probability of regulatory success in at least one of the four markets is better than the probability of regulatory success if they were to submit to only one market.
    6. If top-line data is compelling, then the valuation could reach $10-20B based on the CAR-T valuations and with the understanding that DCVax represents a platform that can be applied more readily to a larger set of indications (i.e. each CAR-T drug that addresses a new target must go through the drug development process and each first-generation CAR-T prep for each patient requires a genetic engineering step, which is not required for DCVax). To be clear, DCVax is easier to produce than first-generation CAR-Ts.
    7. I was reminded that their facility has the capacity for 10,000 patients per year, which is large enough to drive it to the valuations cited above.
    8. The general feel was that the board has greater confidence, optimism, and unity than ever before.
    Along with the key takeaways above, I have a growing sense that the company intends to inflict maximum value at the most advantageous moment for shareholders. A crescendo, with a vengeance.

    Disclosures

    Carlo Rago, PhD owns Northwest Biotherapeutics (NWBO) Common Stock. In addition, Dr. Rago serves
    as a Consultant to District 2 Capital and Bigger Capital. Dr. Rago’s compensation at District 2 Capital
    and Bigger Capital depends on the performance of the securities in their portfolios. District 2 Capital and
    Bigger Capital own both Common Stock and Warrants of NWBO. This review is based solely on publicly
    available information and does not represent medical or investment advice in any way.

    This blog post may contain forward-looking statements, including statements as to anticipated or
    expected results, beliefs, opinions, and future financial performance. The forward-looking statements are
    based on current expectations and assumptions and involve risks and uncertainties that may cause the
    Company's actual experience to differ materially from that anticipated.

    The views contained in this blog post represent the opinions of Dr. Rago as of the date hereof. In
    addition, the efficacy and safety of DCVax-L is only one element in valuing the securities of the
    Company. Investors and other interested parties of the Company are encouraged to do their own analysis
    of DCVax-L and the Company. Dr. Rago reserves the right to change any of his opinions expressed
    herein at any time and for any reason and expressly disclaims any obligation to correct, update or revise
    the information contained herein. The information contained in the blog post may not contain all of the
    information required in order to evaluate the value of the Company or its securities. Investors should seek
    independent scientific or financial advice regarding the efficacy and safety of DCVax-L, the suitability of
    investing in any securities or of following any investment strategies; Dr. Rago is not offering or providing
    such services in connection with this blog post or otherwise making a recommendation to buy or sell
    any of the Company’s securities.

    Bigger Capital Fund, LP, District 2 Capital Fund LP and related entities are long 15 million Northwest
    Biotherapeutics, Inc. securities (stock and derivatives) and are actively trading in its securities. NWBO is a
    microcap company and it is not suitable for the majority of investors. The likely outcome of an investment is
    a loss of principal. Take our opinions with a grain of salt. If you find yourself relying on our views to make
    an investment decision it means you definitely did not do your homework about this situation. Please do
    not rely on our views, instead use the information as a jumping off point to begin your own independent due
    diligence.
    Article originally appeared on (http://biggercapital.squarespace.com/).
    See website for complete article licensing information.
     

    GlobeCitizen

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    While investors are waiting for topline data from DCVax-L Phase III trial, it may be interesting to read Dr. Rgao's study on DCVax-L:

    A Second-Generation Dendritic Cell Cancer Vaccine Preparing to Shine
    DCVax-L efficacy may correlate with tumor mutational burden, suggesting mechanism is operable Carlo Rago, PhD
    July - November 12th
    2018, updated February 18th 2019
    https://www.scribd.com/document/393282167/A-Second-Generation-Dendritic-Cell-Cancer-Vaccine-Preparing-to-Shine
    Highlights


    DCVax-L is a second-generation autologous dendritic cell vaccine that targets potentially all of the neoantigens on a patient’s tumor, a key advantage over first-generation vaccine products that targeted only a single antigen with mixed success.


    DCVax-L newly diagnosed GBM phase III blinded interim results (published May 2018) for the entire cohort and also MGMT-M and MGMT-U subsets compare favorably with historic and contemporary trial results and may improve with additional follow-up.


    The mOS delta between MGMT-M and MGMT-U tumors - an indicator that DCVax-L is working through neoantigens and the proposed vaccination mechanism - compares favorably with historic and contemporary trial results and may improve with additional follow-up.


    Results for patients with partial or complete resection offer the most accurate analysis and compare favorably with Stupp’s 2005 and 2017 SOC.


    Safety is impressive, commercial manufacturing is a surmountable challenge, and the regulatory environment for GBM, a deadly disease with severe unmet need, is favorable.



    With imminent phase III results and emerging mechanism evidence, Northwest Biotherapeutics ($NWBO) may be a severely discounted cancer immunotherapy company at a $100M market capitalization.
    Table of Contents
    Summary Cancer Immunotherapies and Tumor Mutational Burden Quantitative Antigenicity Epitope Spreading Unstable Genomes DCVax-L Phase III Interim and Other Results Other Factors Discussion Conclusion Tags Disclosures About the Author Acknowledgments References
    Summary
    Dendritic cell vaccines are beginning to bear fruit for cancer patients. As they are able to mount broad immune responses to neoantigens, they represent an important tool for cancer immunotherapy strategies. The DCVax-L phase III interim results in newly diagnosed glioblastoma (GBM) patients offer a first look at a second-generation product. Safety is impressive and commercial manufacturing is a surmountable challenge. While we await the formal analysis of efficacy, the interim publication offers fertile data for debate and speculation. First-principles and Occam’s razor suggest there is unrealized value in Northwest Biotherapeutics.
    Cancer Immunotherapies and Tumor Mutational Burden
    Cancer immunotherapies are designed to evoke an immune response against neoantigens, which are the consequence of genetic alterations accumulated over the life of a tumor.
    1–3
    Checkpoint inhibitors were initially tested in skin (melanoma) and lung (NSCLC and SCLC) cancers, which have an auspiciously high number of mutations. It has become clear that the tumor mutational burden (TMB) – often expressed as the number of non-synonymous mutations – is positively correlated with clinical outcomes for immunotherapies. In a landmark study by Le et al, the importance of TMB was demonstrated by the strikingly different clinical outcomes for colorectal cancer patients with mismatch-repair deficient (high mutations) vs proficient (low mutations) tumors using immune checkpoint blockade.
    4
    The correlation between TMB and clinical outcomes for PD-1 blockade extends to a wide range of solid tumors and an equation was derived to predict clinical response rate using mutation number.
    5,6
    Cancers employ immunoediting and modifications of the tumor microenvironment to avert the innate and adaptive components of the immune system, and while the immunoscore
    7
    is emerging as a valuable composite prognostic factor because it surveys functional immune response, TMB remains an important biomarker in cancer immunotherapy and provides context for emerging clinical trial results.
    Quantitative Antigenicity
    The median TMB across various cancer types spans about three orders of magnitude - The number of mutations in MMR-deficient (~1,000s), mutagen-associated (~100s), adult solid (~10s), and liquid and pediatric (few) cancers largely reflects their etiology.
    1
    However, relatively small differences in TMB have been shown to correlate with clinical outcomes. For the purposes of studying the relationship of immunotherapy response rates and TMB in lung cancer, some clinical trials have binned tumors into tertiles representing low (0 to <143 mutations), medium (143 to 247 mutations), and high (>247 mutations) burden and compared outcomes between these groups.
    8,9
    For example, nivolumab monotherapy treatment of patients with small cell lung cancer (SCLC) containing low, medium, or high TMB resulted in 3.1, 3.9, and 5.4 months mOS, respectively. Likewise, treatment with nivolumab combined with ipilimumab resulted in 3.4, 3.6, and 22 months mOS, respectively, for SCLC patients with low, medium, and high TMB.
    8
    Additionally, a substantial mPFS difference of 9.7 vs 4.1 months was shown, respectively, for patients with high vs low-to-medium TMB non-small cell lung cancer (NSCLC) treated with nivolipumab.
    9
    These studies highlight the importance of TMB as a predictive biomarker for response to immunotherapies and suggest a two-fold difference in number of mutations can be clinically meaningful. To be clear, TMB is a proxy for the number of productive neoantigens or antigenic neoepitopes. It is estimated that only one tenth of non-synonymous mutations result in useful targets.
    10
    First, the mutant protein must be expressed, a condition that may eliminate about half of the candidates. And expressed mutant proteins must be either recognized by the immune system on the cell surface in their intact form
    11
    or become processed into peptides compatible with MHC-I or MHC-II in a patient that has the appropriate HLA-type to present the peptides.
    2,12
    Finally, the tumor microenvironment - and perhaps the whole patient - must be permissive to mount an immune response.
    13
    Each neoantigen provides an opportunity to maximize the efficacy of immunotherapy strategies. Checkpoint inhibitors allow pre-existing or adoptively transferred T cells to perform better against their potentially numerous neoantigen targets. First-generation CAR-T strategies designed against only a single neoantigen were able to generate objective responses in various leukemias and lymphomas leading to drug approvals for Novartis, Kite, and Juno. More recently, complete regression of metastatic breast cancer was achieved in a single patient preconditioned with nonmyeloablative immunodepletion using cyclophosphamide and fludarabine and further treated with a combination of a checkpoint inhibitor and tumor-infiltrating lymphocytes (TILs) that recognized neoepitopes derived from only four neoantigens.
    14
    Provenge is a clinically and commercially successful dendritic cell vaccine pulsed against a single antigen for prostate cancer.
    15,16
    An advantage of second-generation dendritic cell vaccines pulsed against whole tumor lysate is their ability to stimulate an immune response to a variety of neoantigens. DCVax-L has the opportunity, in theory, to present all the neoantigens that exist in a patient’s cancer and represents a second-generation approach. It is widely known that more mutations translate to a higher chance of having “winning” neoantigens and strategies that target more neoantigens are more likely to give better outcomes.
    17
    Dendritic cells are professional antigen presenting cells well-suited to exploit all the neoantigens – Along with checkpoint inhibitors and adoptive T cell strategies, dendritic cell vaccine therapy development is on the rise and the value is becoming increasingly evident.
    18–21

    Epitope Spreading
    Immunotherapies have been shown to induce immune responses against additional, non-target neoantigens, including intramolecular or intermolecular spread that may switch between MHC-I or MHC-II restricted responses.
    22,23
    Epitope spreading can be documented in the blood by an increased diversity of TCRs and antibodies specific to tumor antigens. Cancer immunotherapies designed to target a single antigen (e.g. Provenge, Rindopepimut, and first-generation CAR-Ts) only have one shot at inducing antigen spread. On the other hand, dendritic cell vaccines primed against whole tumor lysate as well as checkpoint inhibitors have many chances of amplifying their assault on cancer cells. Epitope spread takes time and new immune-related response criteria may be required to track this important feature of immunotherapies.
    22
    Initiating the immune response and epitope spread with more antigens should control tumors faster as the cascade will more rapidly target a sufficient number of good antigens. Provenge worked with a single antigen and epitope spread was documented, but prostate cancers are slow-moving offering patients time to mount an immune response. Since GBMs are notoriously immunosuppressive and progress rapidly,
    24
    it’s possible that the single antigen (EGFRvIII) that failed in the Rindopepimut trial was simply not enough to drive a sufficient spread to other antigens and it’s likely that vaccine strategies will require many antigens for successful therapy. An increased abundance and heterogeneity of the anti-cancer adaptive immune response may awaken the force of the innate immune system. Epitope spread may also help to counteract genetic instability and heterogeneity, the hallmarks of cancer.
    Unstable Genomes
    Cancer genomes are unstable and there is a considerable genetic heterogeneity among cells within and between tumors.
    25,1
    Intratumoral heterogeneity is associated with reduced overall survival in colorectal cancers.
    26
    Glioblastoma multiforme are notably heterogeneous and they were historically classified into four distinct tumor types, which were more recently refined to three types.
    27,28
    Cancers can escape therapeutic pressure through mutations that have accrued over the life of the tumor,
    26,29–31
    including those that existed before therapy and those that have been induced by chemotherapies (e.g. alkylating or other DNA damaging agents). For example, treatment with temozolomide (TMZ) damages DNA and increases the genetic heterogeneity in a patient’s cancer. In fact, approximately one third of all MGMT-M cancers become MMR-deficient and hypermutable after TMZ treatment.
    32
    The mutations that allow cancers to escape confer advantages and the tumor mutational landscape is able to evolve under the selective pressure of therapy. Much like the triple-drug cocktails that were able to tame the unstable HIV genome, it appears that therapies targeting at least four good neoantigens may be required for durable cancer outcomes - Four good neoantigens or about 40 non-synonymous mutations.
    14
    Adult GBMs overall have a median of 35 non-synonymous mutations,
    1
    but it was shown more recently that there are 400% more mutations in MGMT-Methylated (MGMT-M) than MGMT-Unmethylated (MGMT-U) GBM tumors prior to chemotherapy and radiotherapy.
    33
    MGMT converts O
    6
    -methyl-guanine
    errors back to guanine, which is an important DNA repair function that helps cells maintain genomic integrity - This function is inactivated in MGMT-M GBM tumors, which results in the accumulation of more mutations (both normally and under DNA-damaging therapy), confers a better prognosis, and improves the response to therapies when compared to patients with MGMT-U tumors.
    DCVax-L Phase III Interim and Other Results in GBM
    The phase III interim results for DCVax-L in newly diagnosed GBM patients (when adjusted for time-to-randomization) compare favorably with historic and contemporary results for standard-of-care and portend similar or superior results to Optune, which was recently FDA approved (Table 1).
    34–43,19
    Importantly, censored patients can artificially suppress mOS results, so there is a possibility that the data will improve as follow-up time (mFU) is increased in the DCVax-L trial to achieve parity with historic and contemporary trials (Table 1).
    44
    Since the DCVax-L study is still blinded, the results report the combined cohort, which includes the placebo (n=45), cross-over (n=54), and DCVax-L-treated (n=232) patients.
    19
    Based on the vintage (2008), duration (10 years), number of patients (n=331), patient characteristics, and number of international centers (>80) in the DCVax-L trial, it can be reasonably expected that patients treated with SOC (i.e. placebo in this trial) will fall within the tight range found in all of the large (n>150), relevant Phase III trials that also reported intent-to-treat (ITT) data – However, it’s difficult to estimate the mOS of the DCVax-L naïve/placebo patients (n=45) when many of the SOC that progressed were crossed-over to vaccine treatment, leaving a potentially healthier population where, in contrast, some may have also died before the tumor detectably grew, leaving a less healthy population (Tables 1 and 2). Better estimates of the mOS for the n=45 SOC subset will be informative. Furthermore, but less well-appreciated, is the fact that the crossed-over patients progressed before they started receiving DCVax-L treatment and, in the Phase II trial, 0% of patients (n= 5) that progressed before vaccination were able to mount a vaccine-induced immune response, nor did they have a pre-existing native immune signature; whereas 100% of patients (n=6) with stable disease at the time of vaccination had measureable CTL responses after vaccination.
    19,45
    Furthermore, 20 patients that progressed before randomization (an exclusion criteria for the phase III trial) and entered the informational arm to receive DCVax-L treatment were reported to have a mOS of 15.3 months.
    46
    Patients that made it through the 3.1 month period from surgery to randomization before progressing should fare better than the information arm. This key insight suggests that the crossed-over patients will likely also have a mOS similar to the placebo group. Since patients that progress have a less favorable prognosis, even an intermediate vaccine benefit would be helpful. Because the vaccine may have a much lower immune response rate in patients that progress, comparisons between DCVax-L-treated (n=232) and the combined placebo and crossed-over groups (n=99) may be biologically relevant and offer more statistical power. While there are serious caveats when using the blinded data to estimate efficacy, the MGMT status can be used as a measure of how well therapies perform in relation to tumor mutational burden. Dendritic cell vaccines primed against a whole tumor lysate and other broad-spectrum immunotherapies (i.e. checkpoint inhibitors) are expected to selectively target tumors with more mutations and, therefore, should be more efficacious in MGMT-M tumors. Radiotherapy is known to induce an immune response against cancers,
    47
    and temozolomide is known to selectively kill MGMT-M tumors due to their reduced ability to correct DNA damage caused by alkylating agents. Radiotherapy and temozolomide are used in the SOC of newly diagnosed GBM and provide an advantage to patients with MGMT-M compared to MGMT-U tumors – The mOS differences (i.e. M vs U deltas of 10.8, 6.9, 8.9, 6.5 months) published from 2009-2017 for the SOC arms in four clinical trials show how well radiotherapy and temozolomide exploit methylation of MGMT. If an immunotherapy works well, a significant broadening of the mOS delta between MGMT-M and MTMT-U would be expected. Optune was recently FDA approved for recurrent and newly diagnosed glioblastoma and has achieved impressive results in non-small cell lung cancer, where there is high tumor mutational burden. Optune was originally reported to work by disrupting mitotic processes in cancer cells using radio frequencies.
    48
    However, emerging evidence suggests Optune stimulates the immune system by modifying the tumor microenvironment
    49,50
    and it may be this property that selectively targets MGMT-M tumors, resulting in an improved mOS delta of 14.7 months. The only other published ITT phase III study with such impressive gains for MGMT-M tumors is DCVax-L, which resulted in a mOS delta of 14.9 months; Again, this number includes untreated and crossed-over patients, so the delta for the treated patients is expected to improve when the trial is unblinded, as these 99 patients are expected to give a smaller mOS delta of approximately 6-10 months. Furthermore, since there is a two-fold enrichment of censored patients in the MGMT-M group compared to MGMT-U, it’s possible that the delta provided by DCVax-L will expand with additional follow-up as it did for Stupp’s SOC-defining 2005 trial when it was refreshed in 2009. It will be useful to carefully consider the delta after refresh of the phase III DCVax-L results. All the trials in Table I measure mOS from randomization with the exception of the DCVax-L interim analysis which measures from surgery. This difference in methodology adds an absolute, systematic increase to the results for DCVax-L, which can be easily corrected. The median time from surgery to randomization in the DCVax-L trial was reported as 3.1 months
    19
    and, therefore, the reported mOS numbers for DCVax-L can be reduced by 3.1 months to achieve parity with the trials that started the survival clock later, at randomization. However, this arbitrary clock-start difference does not result in differences in the critical time period from diagnosis to randomization, where different trial strategies may introduce immortal time bias.
    51
    Comparisons between trials may be harder to perform if the trials have different degrees of immortal time bias. Immortal time is the period of cohort follow-up in which the outcome can not occur, by design. In practical terms, this means that the time period before randomization may select for healthier patients as patients that die or progress are excluded, introducing a bias. All the trials in Table 1 have some length of immortal time and, therefore, an associated bias. DCVax-L interim results reported a median of 3.1 months from surgery to randomization. The Stupp et. al. 2017 Optune publication notes a median of 3.8 months from diagnosis to randomization. Since GBM progresses quickly and is deadly, the time from diagnosis to surgery is relatively short. For example, Flanigan et. al. describe a median wait time from diagnosis to surgery of 21-26 days, which would put the critical time from diagnosis to randomization for DCVax-L around 3.8 to 4.0 months. Since the Optune and DCVax-L trials have the same time period between diagnosis and randomization and similar exclusion criteria, the immortal time bias should be similar and should not compromise the comparison of the results. The extent of resection is an important prognostic factor that requires special consideration. In the SOC arm of the Stupp et al 2017 Optune trial, biopsy patients had the worst outcomes followed by partial resection then complete resection with 11.6, 15.1, and 18.5 mOS results, respectively.
    43
    A similar trend was found when SOC was defined in Stupp et al 2009.
    35
    The DCVax-L trial excluded biopsy patients presumably because there was not enough tumor material to reliably create the vaccine. Exclusion of biopsy patients will result in inflated mOS outcomes for the DCVax-L combined cohort, but fortunately Liau et al also published mOS results for patients with partial and complete resections,
    19
    allowing a more direct comparison to Stupp et al that avoids bias due to biopsy patients. Stupp et al reported 15.1 and 18.5 for SOC in partial and complete resections, respectively, whereas Liau et al reported 21.1 and 25.4 for the DCVax-L combined cohort (Table 2). When adjusted for the clock-start methodology differences, the DCVax-L combined cohort results in 18 and 22.3 months mOS – These results give DCVax-L an estimated therapeutic benefit of 3.9 months for patients with partial resection and 5.1 months for patients with complete resection, which compare favorably with Optune’s mOS efficacy (Table 2). Because only subsets of patients respond to even the most successful immunotherapies, the most relevant efficacy signal is often demonstrated in the “long tail,” which is the period of follow-up beyond the median. Medians can entirely mask the benefit to small but important subsets of patients. For example, if the GBM patient subset representing the most favorable prognosis under SOC were shifted to the right by many years, it would have no effect on the mOS of the entire treatment arm if they were already on the right of the median. If DCVax-L is targeting the 400% higher mutations found in MGMT-M tumors and substantially improving the mOS for this subset, it might not appreciably shift the mOS of the entire cohort since these patients largely reside on the right side of the median. The effect of immunotherapies can be unmasked and fully realized by comparison of survival rates for experimental and control arms at key time points beyond the control arm median. As the understanding of cancer immunotherapy matures, future trials may select subsets of patients that are more likely to respond and the median outcomes will become more sensitive signals for efficacy, but medians will always be confounded and may underestimate or entirely miss important gains for patients. Results from DCVax-L compassionate use, informational arm, phase I/II and comparator cohorts are instructive although interpretation is limited by significant caveats (Table 3). Newly diagnosed GBM (ndGBM) that progressed rapidly or recurrent GBM (rGBM) patients have poor prognoses which are reflected in the mOS results (Table 3). When treated with DCVax-L, rapid progressors or rGBM patients in various trials had mOS results of 15.1, 14.7, 11.7, and 15.3 months and these numbers were extended to 17.9 months in rGBM with the addition of toll-like receptor (TLR) agonist therapy (shown in red, Table 3). On the other hand, patients with stable disease in Liau et al 2005 had a mOS of 35.8 months (shown in blue, Table 3). Newly diagnosed GMB and the pronueral and mesenchymal subsets also had favorable mOS results of 35.9, 35, and 37.6 months when treated with DCVax-L combined with a TLR agonist. Notably, the mesenchymal subset is known to have a less favorable outcome with standard therapy, but this subset is particularly well-rescued with the mOS shifting from 14.6 to 37.6 months on SOC vs DCVax-L/TLR agonist therapy, respectively. The striking rescue of the mesenchymal subset is thought to be driven by a more pronounced induction of CD3
    +
    and CD8
    +
    T cell response.
    52
    Other Factors
    Prognostic factors for newly diagnosed GBM include age, tumor size, performance status, extent of surgery, radiation dose, and adjuvant chemotherapy use.
    53
    GBM classification and molecular markers are also important. Mesenchymal have worse outcomes than proneural, for example. MGMT-M and mutIDH-1 are independently associated with better survival and patients with combined mutIDH-1 and MGMT-M seem to survive longer than patients with only one of these markers.
    54
    IDH-1 mutations conferred a large survival advantage compared to patients with wild-type IDH-1 (mOS 3.8 years vs 1.1 years, respectively, and a hazard ratio for death of 3.6).
    55
    However, IDH-1 status has opposing effects on survival and response to TMZ, which should be carefully considered in subset analyses.
    56
    Therapy-induced lymphopenia has also been associated with a reduced survival of up to six months
    57
    and the statistical package for the DCVax-L trial was adjusted to reflect this variable that emerged contemporaneously.
    58
    The DCVax-L interim publication cited other unknown factors for a patient subset (n=100 or about 30% of the entire cohort) with an estimated Kaplan-Meier derived mOS of 40.5 months. There are many emerging prognostic and predictive factors associated with tumor response to immunotherapies that may be contributing to the improved overall survival in this DCVax-L subset population (Table 4). Correlating these immune-factors with mPFS, mOS, survival at various time points, or hazard ratios in various patient subsets may provide early evidence that DCVax-L is working through its presumed immune mechanism. Race, gender, and age have been shown to effect responses to immunotherapies. African Americans respond significantly better than Whites to Provenge (mOS of 45.3 vs 24.7 months, respectively),
    59
    presumably because they have more numerous T cells.
    60
    Males respond better than females to checkpoint inhibitors.
    61
    Older patients appear to respond relatively better than younger patients, at least partly due to lower regulatory T cells.
    62
    While age is a negative prognostic indicator in GBM, the Optune trial showed hazard ratios of .51 and .69 for older and younger patients, respectively, suggesting that treated older patients may be more responsive compared to age-matched controls than are younger patients. These examples support the central role of T-cells in the immune response to cancer and suggest that the T-cells induced by dendritic cell vaccines may show similar differences in these populations. Biomarkers can provide early evidence that DCVax-L is working through the presumed immune mechanism. In ovarian cancer patients, a significant transient increase in serum IFN-gamma and,conversely, a significant transient decrease in TGF-beta was found after vaccination with an autologous dendritic cell strategy similar to DCVax-L.
    43
    Response of various solid tumors to DCVax-D (a dendritic cell vaccine that is directly injected into tumors) is inversely correlated with TGF-beta levels in the tumor microenvironment where patients with low tumor-associated TGF-beta had a measurable systemic CTL response and higher overall survival.
    45
    High TGF-beta in the tumor microenvironment is likely to be a negative predictive factor for response to many immunotherapy strategies. On the other hand, IL8, IL12p40, or TNF-alpha production and CD86 or MHC-II levels on dendritic cells positively correlated with DCVax-D outcomes.
    63
    Also, activated dendritic, CD8
    +
    T, CD4
    +
    T, and natural killer cells were each associated with improved overall survival, whereas the number of regulatory T cells and MDSCs were associated with reduced overall survival in colorectal cancer.
    26
    These biomarkers may be useful for interpretation of DCVax-L results. Neoadjuvant immunotherapy is an emerging idea that aims to take advantage of the more numerous neoantigens that exist prior to surgery.
    64–66
    Interestingly, in the Optune trial, there was an inverse relationship between extent of resection and improved hazard ratios, where biopsy, partial resection, and total resection gave .50, .56, .70 hazard ratios, respectively, suggesting that immune modulation by radio frequencies may have a relatively larger impact when there is more tumor present. It will be worth following neoadjuvant studies further to see if there is a correlation of tumor burden and response to immunotherapies. In any case, it will be useful to note the hazard ratios for extent-of-resection subsets in the DCVax-L trial. Notably, DCVax-L’s companion product, DCVax-D, is a neoadjuvant strategy. DCVax-L might be expected to differentially modify outcomes in the patients with factors that modulate the immune responses and these differences between patient subsets might be detectable in the interim or unblinded analyses. Correlation of immunoscore, TMB, and MGMT methylation status with DCVax-L efficacy will give insight into the dependence on functional immune responses and the instigating somatic mutations. Other subset analyses may also provide insight into the immune mechanism. For example, did the seven African Americans in the trial fare better than Whites? Does the older population witness a significant improvement to overall survival compared to age-matched historic and contemporary controls? Are males responding better than females? Are these effects visible by hazards ratios? While these are not requirements, they may contribute to the evidence that DCVax-L is a bona-fide immunotherapy.
    Discussion
    Extensive preclinical and clinical data show exactly how DCVax-L operates as an immunotherapy. Along with favorable mOS data and survival rates at 3, 4, or 5 years, any evidence that DCVax-L is operating through the proposed immune mechanism in the ongoing phase III patients will be highly favorable for regulatory decisions. While the survival benefit is key, it will be useful to monitor the relationship between DCVax-L efficacy and other immune factors in the interim and final analyses for mechanism signals .
    DCVax-L efficacy is improved with the addition of PD-1 blockade
    67
    and further improved with combined PD-1 blockade and suppression of tumor infiltrating myeloid cell (TIM) function.
    68
    These gains were demonstrated in models with high tumor burden, immunosuppressive tumor microenvironments, and poor prognosis, which – to some degree – emulates patients that have progressed. This triple-combination immunotherapy strategy effectively counters the tumor’s attempt to avert the independent effects of each component. These findings provide hope that it will translate to clinical gains for both stable and progressed GBM patients and highlight DCVax-L as an important platform that will allow clinicians to rapidly optimize combination chemo-immunotherapy strategies.
    69–71
    It will be interesting to compare the relative efficacy of neoadjuvant DCVax-D and post-surgical DCVax-L dendritic cell vaccine strategies in future trials, although these distinct approaches may have different optimal combination strategies. CancerCommons and the Musella Foundation for Brain Tumor Research are non-profit organizations aiming to more rapidly test therapeutic hypotheses by facilitating small, rigorous clinical trials that seek large efficacy signals. DCVax-L development would benefit from these strategies, perhaps in the right-to-try setting, and the best results could be used to inform larger phase III clinical trials. By all measures, the safety profile of DCVax-L looks stellar. Importantly, GBM pseudoprogression is correlated with improved survival
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    and the DCVax-L results may give early insight into the considerations that may be relevant to developing modified response criteria and safety monitoring. Response criteria and safety monitoring flexibility may be desirable as the immunotherapy field moves into more complex double-, triple-, and chemo-immunotherapy combinations.
    69–71
    The FDA, by law, is afforded flexibility when considering potential treatments for diseases with severe unmet need.
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    Likewise, the EMA gives special consideration to areas of unmet need. The DCVax-L trial was originally designed and powered for progression free survival as primary and overall survival as secondary outcomes. It’s not unreasonable to expect regulatory agencies to allow use of survival (e.g. mOS) in place of progression (e.g. mPFS), as survival is the gold-standard and most important outcome. This is particularly likely considering the FDA fully approved Bevacizumab for recurrent GBM, where it failed a Phase III trial for the primary outcome (mOS) but showed an improvement to a secondary outcome (mPFS).
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    While decision-making will rely on standards and the preponderance of evidence, regulatory leniency will not be surprising in the context of GBM, a deadly disease with severe unmet need.
    Conclusion
    Dendritic cell vaccines are designed to exploit antigens on cancer cells. The expansion of the mOS delta between newly diagnosed GBM patients with high (MGMT-M) and low (MGMT-U) tumor mutational burden suggests DCVax-L may be working through neoantigens and the proposed mechanism. Checkpoint inhibitor, MDSC suppression, Treg suppression, TGF-beta inhibitor, TLR agonist, cytokines and other strategies may further unleash DCVax-L efficacy. The regulatory environment for glioblastoma is highly favorable and the DCVax-L mechanism is tractable, which will allow rapid optimization in follow-on studies as well as an opportunity for agencies to routinely reassess the value for patients. The DCVax-L safety record is impressive and demand under the right-to-try legislation may challenge manufacturing capacity. DCVax-L is primed to be a landmark for dendritic cell vaccines and cancer immunotherapy and will, hopefully, provide a new treatment option for glioblastoma patients.
    Contemporaneous to Embargo
    Dr. Liau’s group recently published an abstract for the upcoming Society for NeuroOncology meeting that shows dendritic cell vaccination in combination with a TLR agonist for GBM patients (WHO Grade III and IV) results in a mOS of 54 months compared to 11 months for the placebo control.
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    Furthermore, the mOS delta between MGMT-M and MGMT-U for the entire cohort was 38 months (57 vs 19 months,
    respectively). Improved mOS and, particularly, expansion of the M vs U delta with addition of TLR agonists to dendritic cell vaccination provide further evidence that the mechanism is operable.
    Tags
    Mutation, Tumor Mutational Burden (TMB), Dendritic Cell Vaccine, DCVax-L, CD8
    +
    Cytotoxic T Cells, CD4
    +
    Helper T Cells, B cells, Natural Killer Cells, Personalized Medicine, Quantitative Immunotherapy, Cancer Immunotherapy, Immuno-oncology, Immuno-editing, Central Tolerance, Peripheral Tolerance, Biomarkers, Neoadjuvant Immunotherapy, MGMT, Methylated, GBM, Glioblastoma, Radiation, Temozolomide, CCNU, Alkylating Agent, Provenge (Sipuleucel-T), First-generation CAR-T, Tumor Infiltrating Lymphocytes (TILs), Pembrolizumab (Keytruda), Checkpoint Inhibitors, CTLA-4, PD-1, PDL-1, Cancer Genome Atlas Research Network (CGARN), Stupp, SOC, Optune, Manufacturing, COGS, Market Size, Pricing, Vogelstein, Diaz, Jaffe, McDonald, Merkel Cell, Future Trials, Rare Pediatric GBM, Priority Review Voucher (PRV), $NWBO, Northwest Biotherapeutics, Open Science Movement.
    Disclosures
    Carlo Rago, PhD owns Northwest Biotherapeutics (NWBO) Common Stock. In addition, Dr. Rago serves as a Consultant to District 2 Capital and Bigger Capital. Dr. Rago’s compensation at District 2 Capital and Bigger Capital depends on the performance of the securities in their portfolios. District 2 Capital and Bigger Capital own both Common Stock and Warrants of NWBO. This review is based solely on publicly available information and does not represent medical or investment advice in any way. This white paper may contain forward-looking statements, including statements as to anticipated or expected results, beliefs, opinions, and future financial performance. The forward-looking statements are based on current expectations and assumptions and involve risks and uncertainties that may cause the Company's actual experience to differ materially from that anticipated. The views contained in this white paper represent the opinions of Dr. Rago as of the date hereof. In addition, the efficacy and safety of DCVax-L is only one element in valuing the securities of the Company. Investors and other interested parties of the Company are encouraged to do their own analysis of DCVax-L and the Company. Dr. Rago reserves the right to change any of his opinions expressed herein at any time. The information contained in the white paper may not contain all of the information required in order to evaluate the value of the Company or its securities. Investors should seek independent scientific or financial advice regarding the efficacy and safety of DCVax-L, the suitability of investing in any securities or of following any investment strategies; Dr. Rago is not offering or providing such services in connection with this white paper or otherwise making a recommendation to buy or sell any of the Company’s securities.
    About the Author
    Dr. Carlo Rago received his PhD in Cellular and Molecular Medicine at the Johns Hopkins School of Medicine and trained as a post-doctoral fellow in the Ludwig Center for Cancer Genetics and Therapeutics at Johns Hopkins where he was the first to demonstrate the dynamics of circulating tumor DNA (now called liquid biopsies)
    77
    and developed early genome editing techniques
    78
    to facilitate gene function studies and drug discovery. These and other scientific contributions have found widespread use. Carlo was also instrumental in the formation of a global federation of disease-focused foundations, called the Duchenne Alliance, where he served as their scientific director and initiated their venture philanthropy program. Dr. Rago’s software company, OpenOnward, was the first to offer crowd-funding of drug development projects in a secure, online environment and the DuchenneDashboard helped empower the community of foundations to identify and fund the most promising therapies and clinical trials for Duchenne muscular dystrophy. Dr. Rago’s privately held biotech company, DMD Therapeutics, was named on the list of top 20 life sciences companies to watch in 2018 for their preclinical development efforts. Carlo has a passion and deep understanding of cancer-immunotherapy and gene therapy strategies and works with the investment community to identify biotechnology opportunities with the most transformative potential.
    Acknowledgments
    The author would like to thank Zotero reference manager, Mozilla FireFox web browser, and the open science movement for facilitating the free communication of scientific information.
    References [omitted]
     

    GlobeCitizen

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    I have urged the company to hire an Wall Street insider to promote the company. Now the company finally hired a WS insider as its IR guy and an vice president. It is a concrete move as we are waiting for topline data to be released anytime from now to the next three months.
    NW Bio Hires David Innes As Vice President, Investor Relations

    PR Newswire
    February 26, 2019
    31 Years Managing Portfolios At Several Major Wall Street Firms, With Emphasis On Biotech">31 Years Managing Portfolios At Several Major Wall Street Firms, With Emphasis On Biotech

    BETHESDA, Md., Feb. 26, 2019 /PRNewswire/ -- Northwest Biotherapeutics (NWBO) ("NW Bio"), a biotechnology company developing DCVax® personalized immune therapies for solid tumor cancers, today announced that it has hired David Innes as Vice President, Investor Relations.


    Northwest Biotherapeutics Logo (PRNewsfoto/Northwest Biotherapeutics)
    $175 million in assets with a concentration in emerging biotech companies, including as an advisor to many shareholders at NW Bio.&nbsp; Prior to Oppenheimer, he spent 20 years at UBS, including 10 years as a Vice President of Investments.">Innes comes to NW Bio with over 31 years of managing portfolios at major Wall Street firms, and a degree in biology. For the last 10 years, Innes has worked as Senior Director-Investments at Oppenheimer & Co., LLC. At Oppenheimer, Innes managed over $175 million in assets with a concentration in emerging biotech companies, including as an advisor to many shareholders at NW Bio. Prior to Oppenheimer, he spent 20 years at UBS, including 10 years as a Vice President of Investments.

    Innes noted, "After decades of focusing on small to mid-cap biotech and biomedical companies, I was attracted to NW Bio by what I believe is their broad potential, due to their approach to addressing the complexity of solid tumors which comprise most cancers. Their DCVax technology is precision-tailored to a patient's cancer, while also designed to mobilize a broad-spectrum attack on the cancer. As such, I believe NW Bio's DCVax technology has the potential to be a meaningful therapy for many types of solid tumor cancers."

    "I am honored to be joining NW Bio at this pivotal time in the Company's history. I look forward to further strengthening the relationships with both current and prospective retail and institutional shareholders, as well as communicating this DCVax immunotherapy's potential to an ever broader marketplace."

    Linda Powers, CEO of NW Bio, noted, &quot;We are pleased to have someone of Dave's experience in the biotech investment community joining us.&nbsp; We see this as an important initial step in expanding our team with first class personnel as we move toward completion of the Phase III DCVax&reg;-L trial for GBM and initiation of Phase II DCVax&reg;-Direct trials.&nbsp; Welcome aboard Dave.&quot;">Linda Powers, CEO of NW Bio, noted, "We are pleased to have someone of Dave's experience in the biotech investment community joining us. We see this as an important initial step in expanding our team with first class personnel as we move toward completion of the Phase III DCVax®-L trial for GBM and initiation of Phase II DCVax®-Direct trials. Welcome aboard Dave."

    About Northwest Biotherapeutics ">About Northwest Biotherapeutics

    Northwest Biotherapeutics is a biotechnology company focused on developing personalized immunotherapy products designed to treat cancers more effectively than current treatments, without toxicities of the kind associated with chemotherapies, and on a cost-effective basis, in both North America and Europe. The Company has broad platform technologies for DCVax® dendritic cell-based vaccines. The Company's lead program is a 331-patient Phase III trial of DCVax®-L for newly diagnosed Glioblastoma multiforme (GBM). GBM is the most aggressive and lethal form of brain cancer, and is an "orphan disease." The Company is also pursuing a Phase I/II trial with DCVax®-Direct for all types of inoperable solid tumor cancers. It has completed the 40-patient Phase I portion of the trial, and is preparing for Phase II portions. The Company previously conducted a Phase I/II trial with DCVax®-L for metastatic ovarian cancer together with the University of Pennsylvania.
     

    GlobeCitizen

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    Since David Innes took the reins as IR person of the company, the stock price has appreciated about 42% in less than two weeks. As topline data may be released any day now, the trend is highly likely to continue. Considering the huge market potential of DCVax platform, the current price is still outrageously undervalued.

    It feels like tea time now waiting for champagne to pop.
     

    newer

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    Have fun as it lasts.

    Since David Innes took the reins as IR person of the company, the stock price has appreciated about 42% in less than two weeks. As topline data may be released any day now, the trend is highly likely to continue. Considering the huge market potential of DCVax platform, the current price is still outrageously undervalued.

    It feels like tea time now waiting for champagne to pop.
     

    GlobeCitizen

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    Thank you for your kind words. I have been in this big for years, bought heavily in teens and twenties to average down.
    UCLA Seminar with National Cancer Institute director Dr. Norman Sharpless, the newly appointed acting chief of FDA
    Talk title TBA

    Date: April 17, 2019 12:00 PM - 1:00 PM
    Location: NRB Auditorium
    Los Angeles, California 90095

    https://cancer.ucla.edu/Home/Components/Calendar/Event/2358/1195

    Join us in welcoming Norman E. Sharpless, M.D., Director of the National Cancer Institute, to the UCLA Jonsson Comprehensive Cancer Center.

    He will be participating in a ONE DAY ONLY VISIT to UCLA on Wednesday April 17, 2019. Dr. Sharpless will be presenting a seminar that is open to all UCLA staff, faculty and leadership.

    Please be sure to save the date! More information to be forthcoming.

    Date: Wednesday, April 17, 2019
    Location: NRB Auditorium
    Time: 12:00 p.m.
     

    newer

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    Admire your deep research and patience. Wish you will be rewarded dearly.

    Thank you for your kind words. I have been in this big for years, bought heavily in teens and twenties to average down.
    UCLA Seminar with National Cancer Institute director Dr. Norman Sharpless, the newly appointed acting chief of FDA
    Talk title TBA

    Date: April 17, 2019 12:00 PM - 1:00 PM
    Location: NRB Auditorium
    Los Angeles, California 90095

    https://cancer.ucla.edu/Home/Components/Calendar/Event/2358/1195

    Join us in welcoming Norman E. Sharpless, M.D., Director of the National Cancer Institute, to the UCLA Jonsson Comprehensive Cancer Center.

    He will be participating in a ONE DAY ONLY VISIT to UCLA on Wednesday April 17, 2019. Dr. Sharpless will be presenting a seminar that is open to all UCLA staff, faculty and leadership.

    Please be sure to save the date! More information to be forthcoming.

    Date: Wednesday, April 17, 2019
    Location: NRB Auditorium
    Time: 12:00 p.m.
     

    GlobeCitizen

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    Thank you, and wish you the best for whatever you do and is going to do !
     

    GlobeCitizen

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    FY: Northwest Biotherapeutics' therapeutic cancer vaccine platform DCVax is developed based on dendritic cell, the master regulators of the immune response, which was discovered by our Canadian scientist Dr. Ralph M. Steinman, etc. On October 3, 2011, the Nobel Committee for Physiology or Medicine announced that he had received one-half of the Nobel Prize in Physiology or Medicine, for "his discovery of the dendritic cell and its role in adaptive immunity". The other half went to Bruce Beutler and Jules A. Hoffmann, for "their discoveries concerning the activation of innate immunity".
    https://en.wikipedia.org/wiki/Ralph_M._Steinman
    So as a proud Canadian and an investor of nwbo, I am specially thankful for their discovery.
     

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    About 4 minute video clip to watch about Dr. Linda Liau, the inventor of DCVax-L:
    https://spectrumnews1.com/ca/la-west/la-stories/2019/04/08/la-stories--renowned-brain-surgeon-dr--linda-liau
    LA Stories
    'I Love What I Do' - Internationally Renowned Brain Surgeon Dr. Linda Liau
    By Spectrum News Staff
    PUBLISHED 10:22 AM ET Apr. 08, 2019

    Spectrum News 1 Anchor Giselle Fernandez and LA Stories spent time with internationally renowned brain surgeon Dr. Linda Liau at the University of California Los Angeles. Dr. Liau grew up near Los Angeles' inner city and today, she’s recognized for developing and refining innovative treatments to tackle glioblastoma, the most aggressive and lethal type of brain tumor.

    Her innovative medical procedures are saving the lives of patients previously given no hope who come to her from all over the world for care. She shares with Giselle what drives her devotion to change the odds and save as many lives as possible, proving that what seems impossible is possible.

    Dr. Liau knows first-hand the pain of this diagnosis. She lost her own mother to breast and brain cancer.

    Liau is also the chair of the Department of Neurosurgery at the David Geffen School of Medicine at UCLA. In a field dominated by men, she is only the second woman in the United States to chair an academic department of neurosurgery.
     

    GlobeCitizen

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    It may be the same ole and the same ole or maybe something earth-shattering. JFYI:
    At ASCO Expert Theater nwbo CEO and CTO will present on 2 June
    Update on DC Vax
    Time: 4:15 PM - 5:15 PM
    Company: Northwest Biotherapeutics
    Presenters: Linda Powers, Chief Executive Officer, Northwest Biotherapeutics
    Marnix Bosch, Chief Technical Officer, Northwest Biotherapeutics

    https://meetings.asco.org/am/industry-expert-theater
     

    GlobeCitizen

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    Increased activities - - a prelude to something concrete
    "
    Face it Ladies and Gentlemen: Everybody in this board or the like who posts, either endlessly 24/7 for years or occasionally, or who comes and goes all the time, is aiming at cheap shares either directly or indirectly (those who do so by heeding to the work orders of their funds so they may not be direct shareholders of this wonderful company and who can readily claim to have no shares at all despite posting tirelessly, either part of the wolfpack or not).

    The problem or truth is the greed, which on one hand prevents an ordinary retail investor from seeing the forest for the trees despite being surrounded by cheap shares. In this regard, those without shares but posting tirelessly have accomplished their work preventing the share price from having higher pressure to rise; it's the same problem of the greed, which also prevents the funds from taking initial and/or substantial positions before everything is crystal clear by pivotal data despite their tireless efforts preparing the market to the eventuality of a successful trial. When the time comes, they may still debate the results hoping that the market cannot distinguish between days and nights, so they may still argue the share price can only rise to such a level such as $1 or 2$ even if the market having a stellar data in its face because the price simply cannot jump too high from a relative low level such as $0.3 or $0.5. What a faulty logic!

    The utmost purpose is of course cheap shares. When they work hard to warn the market, they will be busy accumulating the cheap shares by their definitions. With some undeniable data, they may also forget the market may be manipulated in some conditions but it cannot be in other conditions and forever.

    So the chance is that they will be overwhelmed by a tide wave of huge share price normalization supported by the general market. As to how high the share price can rise, the best reference is clearly the market cap of other similar companies, and such examples are plenty, anywhere in the range from around $5 billion to $20 billion.

    Yes, we may not be able to take over a market cap of $10 billion (roughly equal to $10 ~ $15 per share on fully diluted base) for example right away or within a short period of time after undeniable data are released, but to say $1 or $2 is the ceiling on such occasion is utterly absurd, but if the reality is otherwise, then get dry powder ready, and there is not other way to do it: get in big!

    Too many people are hoping to get in cheap without taking any due risks, and for that something is definitely not right!

    Are the two still blinded data sets released still not enough to de-risk? Then I would say it's the greed and a dumb greed that has blinded you!

    BTW, I still expect a huge short squeeze is in the working!
    "
     
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