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I am suspecting this may be the case. In the weeks before the stock hit $2.50 a couple of years ago, I was contacted by Fidelity about loaning out my shares (I refused). I think that may have been an indicator of a large number of shorts making plans for a later takedown (which obviously happened in a big way on May 10). I had not had any messages from Fidelity about loaning out my shares again until a couple of days ago. Makes me think we might see a rise in price through submission, with shorts piling on (with lots of FUD) after submission while we wait for an approval decision and have no news. Just a guess but seems to fit what happened before.
Thanks Doc. My hope is also that the unique circumstances of the DCVAX trial work in favor of approval based on the JAMA data. My original post was in part just a feeler to see if anyone had ideas on the possibility that the company might have been able to obtain patient-level data. Do we know if any prior trials used as ECAs in teh JAMA article were run by pharmas that the company is working with on Combo trials (i.e., potential partners)? That would be the best option for data sharing. I haven't kept up with things enough to know.
I haven't posted for a while but have been skimming posts. I was thinking about the recent FDA comments about using external controls for approvals. As much as I dislike the persistently and unjustifiably negative comments of some posters, I do have to admit that I also have some concerns about the FDA saying patient-level data are needed for approvals based on ECAs. What NWBO did in their JAMA article in essence reproduced patient-level data as best they could from the group level data reported in prior publications. This is not true patient-level data and still could be biased despite the statisticians many efforts to fight against possible bias. The fact that JAMA reviewers thought this was good enough for publication gives me at least some hope for FDA approval despite the recently published FDA comments. The fact that GBM is an FDA-designated orphan condition with no new interventions in years, that trials for orphan conditions have more lenient rules for approval, that DCVAX has a very good safety profile (so relatively little benefit has to be shown for a cost:benefit analysis to favor approval), and that the FDA Orphan Condition Office should have an incentive to try to find a way to approve DCVAX for GBM also all give me hope for eventual approval. That said, I wonder if the company has been trying to obtain patient-level data from prior trials to use in their approval package? Might this have contributed to how long it has taken them to get the MAA submitted? There has been a move in recent years both here and in Europe to make full trial datasets publicly available to qualified researchers (NIH now mandates this for NIH funded studies). Here are some ways that I think NWBO might obtain patient-level data from prior trials: 1) simply request it from the Principal Investigators of prior trials (if these trials received NIH funding, they might be inclined to comply), 2) If anyone who is a Co-Investigator on the DCVAX GBM trial or who is an NWBO consultant worked as an investigator on prior trials, maybe they could facilitate obtaining data from prior GBM trials, 3) If any prior trials were run by companies that NWBO is now pairing with for combo trials (and potentially considering partnership), maybe these companies would make their prior trial data available. I hope that NWBO has at least made an effort to obtain patient-level data because I think this would greatly facilitate FDA approval chances. Without this, I think the best we might hope for is a conditional DCVAX approval by the FDA with some requirement of an additional phase 4 study. I am long and hopeful....
Onco - I agree it was not a peer-reviewed scientific presentation at ASCO, but that does not take away from the science presented. I have no idea whether these claims of tissue agnostic approvals will happen or how likely they are. However, what excites me the most about the ASCO presentation is that clearly the company and scientific advisors have been working on defining and documenting the MOA of DCVAX. Having an identified MOA will help offset the likely criticisms of the phase 3 trial design (use of external controls) during the approval process for GBM with regulatory authorities. In the absence of a MOA, it would be much easier for FDA advisors to simply claim the positive phase 3 results were the result of selection bias and differences between the DCVAX sample and prior phase 3 trials used as external controls. Now that argument is much less convincing since we can see why DCVAX should have been effective in the trial.
Thinking out of the box - could NWBO be creating a new company (possible merged with another small relevant company) that NWBO shareholders will get stock in based on the level of their NWBO holdings? New stock price could be arranged to be high enough to get uplisted ASAP (e.g., $4-5 /share). This would open up institutional investors. What do y'all think? Might this cause problems for naked shorts to the extent they exist, and even for regular short holders. I am just thinking in context of lawsuit, they may be trying to do something else aggressive and dramatic to address stock manipulation. That could be the big other news per Fireman's comments.
Gary - Agree that the breadcrumbs could be from rye, sourdough, or plain white bread. We just don't know for sure. Much as I like the company, there is just not much there other than a a few employees, a chest of patents, and some data. They are just not suited for commercialization. I know they are currently using outside experts to prepare regulatory documents, but they don't have to be doing that. Objectively I have to say going it alone looks like a big mistake that is way more risky than getting BP experts on their side and getting the deep pockets of BP to help in development not only of DCVAX but direct as well. Would a smart lawyer who really wants DCVAX out there to be used by patients sooner rather than later be likely to make that mistake if opportunity comes knocking? It would take a massive ego to do that, and I just do not know what LP is like. I will admit Amarin apparently did that, refusing a BO when one was offered because they thought they were way more valuable than they were. But, they were a much bigger company with house expertise that led them to believe they could go it alone if needed. We will know one way or the other by the ASM I guess.
This is all speculation but sometime breadcrumbs indicate a loaf of bread is present. I was doing a 6 hour drive this week and started thinking about the breadcrumbs we have. Assuming the company's main goal is to get DCVAX out there to help patients, which I believe is the case, consider the following:
1) Objectively NWBO does not have the in-house personnel or expertise to get FDA approval for or market DCVAX. They need help desperately, and there are no signs of any plans to hire more personnel. A partnership or buyout (BO) would be an obvious solution. The company also has almost no financial resources left and for some reason did not request that many more shares to be authorized at the upcoming ASM beyond what is necessary to convert the C's. They are running on fumes and need capital. Why would the company not be pursuing partnership or BO? That would make no sense.
2) The company does not have the funds to do further trials (direct). Partnership or BO would be an obvious solution.
3) The company already has a working relationship with BPs from their combo trials, and a successful P3 trial of combos could extend the market for their agents. There is money to be made for BPs so why not invest in NWBO? Beyond combo uses, DCVAX for GBM as stand-alone would also create revenue. Again, why not invest if you are a BP?
4) BP may have been hesitant that there might be something wrong with the trial results. Having a JAMA level journal sign off on them may have helped them feel a bit more comfortable about how results would be received by reviewers at the FDA and with likelihood of approval (which I think is a done deal given GBM's orphan status and current FDA thinking on ECAs for such conditions). Keep in mind the company has known the JAMA article was accepted since late August, so they could have privately shared that news with BPs in early September. Negotiations could have been ongoing for months. The company has also had their full data for well over a year now and could have provided the raw study data under an NDA long ago to prospective partners/buyers. A partnership or BO now would not in any way be rushed - there has been plenty of time for this.
5) However you may feel about bold predictions, Fireman has been a legit and level-headed poster for a while. Suddenly, he notes a hedge fund friend contacted him, and after that, he has been very cagey. Doing big deals involves lots of people, and word clearly sometimes gets out on the street before big things happen even when things are supposed to be private. It happens. So, I do not find Fireman's implied claims that he knows something big that will increase the stock price to the $5 range in the next week or so to be implausible. I understand his being cagey - it is appropriate. I also find his predictions remarkably specific for total BS. Why would he do that with no history of being a price manipulator by past outrageous statements? What could "big news" be? MIA approval? - no, that is expected and not really major news. Submission to MHRA or FDA? No - again, expected and doesn't really change the current company situation. Surprise lawsuit? - done. Uplisting? - no, not possible right now. It is too early for another publication. I find it hard to think of events that would be "big news" other than the options above, or a partnership/BO.
6) Why was the lawsuit filed when it was? Might they have been hoping to clear the runway and reduce stock price manipulation prior to big pending news? Getting the stock price up a bit would certainly help with bad optics for the BP buyer or partner who might be accused of overpaying. The lawsuit provides a good reason for claiming the current stock price does not reflect the company's underlying value. Again, might this suit smooth the runway for something big? If the company wins the suit, it will be years before they see any damage award. This was not an effort to keep the company afloat short term. On the other hand, if a BO was pending, we might wonder why NWBO would even bother with the suit. The company would soon no longer exist. Maybe this would argue more for partnership than BO?
7) Why was LL's recent talk on combo therapy pulled so fast? Some indicated they had heard that the company had requested this. Why? They allowed the 5/10 talk to be kept up. If Topher Tink is to be believed, Al Musella said he could not explain why it was pulled but might be able to do so today. This didn't happen but why would AM give such a specific time for being able to explain? Pending news that he is aware is coming out soon? He seems pretty plugged in to the company so it is not inconceivable that he was asked to pull the talk down with a confidential explanation of why and when this might change. Why would it be pulled? If a BP is partnering or doing a BO of NWBO, maybe the talk included what the BP now considers proprietary information?
8) Is whatever to be announced coming later than expected? Maybe it is to be triggered by another event. Maybe MIA approval which is also late?
9) Why was the ASM scheduled for the last day possible this year? Clearly they wanted to at least look like they were trying to have an ASM this year for compliance purposes. Maybe they waited as long as possible to give time for some big news to be announced that could then be discussed at the ASM (maybe beyond the JAMA article)?
10) The fact that the company requested an authorized share increase (without obvious buyers) suggests that they may have wanted to convert everything into regular shares rather than C shares. Might this change be necessary in a BO situation (e.g., what if you had a BO and some stock holders had shares that could not actually be issued because they exceeded authorized shares?)
11) Maybe LP is smarter than many give her credit for. Assuming there is a partnership and she has been specifically trying to get at least $5 per share in added value for the company, that number may not be random. Once a partnership is announced, the stock price should quickly hit the company value implied in the the deal, and at $5, would be high enough to quickly uplist. Obviously this is irrelevant in a BO scenario.
13) Arguing against both a partnership or BO might be the recent purchase of C shares by JJ. How could this be done without him being accused of insider trading? The company obviously has to keep the lights on and pay all their bills even while waiting for an influx of cash. Would it be acceptable under those circumstances for JJ to buy C shares to help keep them afloat temporarily? Is it possible that only LP and her lawyers knows what's going on if there is a partnership or BO in the works? Might the board members be unaware of this yet?
I give it until the end of December before I start thinking Fireman is full of it
FE - I agree that no one knows the timing of anything coming up. However, wouldn't you agree in principle that the company is likely engaged in partnership negotiations? They have good P3 trial results likely approvable given the orphan condition status of GBM, but lack the financial resources, personnel or expertise to actually market the drug or even efficiently shepherd it through the FDA process. I see no path forward but partnership/BO to gain stable financial backing, particularly since their requested increase in authorized shares is relatively small. They are also already working with BPs on combo trials, so clearly there is already a working relationship with them. I think the only question is how soon any news comes.
My guess is that if the Rett indication is approved by the FDA and the drug marketed, the drug will start being used off label for AD. A good parallel is Neurontin, which was indicated for seizures but generated much of its revenue from wide off-label use for chronic pain. Off-label use will bring in extra revenue even before any AD indication is approved by the FDA. Getting the drug approved for Rett is very important.
What they reported were very simple statistics, and I am assuming from what the company said that this was due to time constraints. I think you are right on about needing a MMRM (mixed effect model repeated measures) analysis. That could address the drop-out issue in a reasonable way but would not necessarily hurt the results - this analysis could even improve the p values on the primary outcomes slightly.
Your point about needing increased statistical power of the full sample is a reasonable argument, but depends on whether there was increased efficacy with greater dose as was clear in past studies. You sound like you do research. I am sure you know that if there is a dose response effect, the 50mg group would show higher significance than was reported for the combined group and would be in effect pulling up the significance of the "laggards" in the 30mg group (which may not be significant). FWIW - My prediction is that 50mg showed efficacy on primary endpoints well under p<.025.
Given the dose response seen in prior work (50mg always more effective), the significant combined data presented is likely due to very strong results in 50mg group (highly significant) and weaker results in the 30mg group (may be close but not quite significant). It would have been easy to break it out that way. I have to wonder whether they chose to present the combined groups (any exposure to the drug) because it bumps up their intervention sample to over n=300, which would be more convincing as a P3-size trial sample. With all of the highly critical comments posted over the past 24 hours I think there is a "missing the forest for the tress" issue - you don't get results like they reported if there is not a real signal. The minimal data presented so far may be confusing without adequate context and explanation, and there may be errors in specific numbers, but the bottom line is the drug clearly works. If they can show that 50mg works better than 30mg and that achieved drug levels correlate with efficacy (and other findings getting at the idea that the hypothesized MOA is correct), I think the drug has a shot at approval but maybe with a P4 follow-up.
Unless you impute, how do you propose to do ITT analyses on changes from baseline to 48 week follow-up if you do not have follow-up data? Missing follow-up is why they were not included in the analysis.
Per clinicaltrials.gov, the primary outcome is: Reduction in cognitive decline assessed from baseline over 48 weeks with ANAVEX2-73 compared to placebo using the Alzheimer Disease Assessment Scale-Cognition (ADAS-Cog)
They are looking at the drug effect overall not the dose effect in primary analyses. This is not a "fail per protocol".
The actual talk is posted. Interesting that these results were combining both dosage groups (30 and 50mg). Almost assured that data in the 50mg group were much stronger than what was reported in the PR.
https://www.anavex.com/_files/ugd/79bcf7_669721c3ce0e4868b5c52ba343b24064.pdf
Thanks for posting the full filing. Sure looks like they have the defendants caught with their hands in the cookie jar. An immense amount of effort went into detecting this, and the examples provided show they have a huge amount of detailed trading information even before discovery. Kudos to the company.
If NWBO wins a $500,000,000 judgment (random number for an example), does that value translate into increased overall company value of 0.5 billion, which should then be reflected in the stock price?
I am confused. Thermo thinks this week will be interesting and Fireman said he was meeting with a friend this weekend who had interesting info, and he seems to have disappeared since then (can't talk?). I have no idea what good news might be coming, but it does have me wondering if there might be something to the rumors. Just doesn't make a lot of sense to me that they would announce a straightforward ASM if big new was pending.
Maybe NWBO fired them for poor planning for PR of initial TLD release at NYAS.
I have assumed for months that the delay in ASM was so they would have the good news of the JA to talk about at the meeting. Made no sense to delay it otherwise. JA is here and 4 days later no ASM announcement. I still have to believe the only reason to still delay it is to make sure they have something meaningful to discuss. If not the JA, what is it???
She is seeing from the article that PFS, the original primary endpoint, was a little worse in the patients originally assigned to DCVAX, but this is known to be an artifact of the immune response to DCVAX. Because of this, the endpoints were changed to OS which necessitated a change in the plan of analysis. Good methodological reasons to do so and the company used a very sophisticated approach to analyzing the OS data against historic controls that is consistent with FDA guidelines, especially for an orphan condition like GBM. Given its orphan status, no toxicity (very safe) and signs of a positive response to DCVAX even in recurrent GBM (i.e., benefits outweigh the costs), I see no reason why this won't get approved. The FDA mandate for orphan conditions is to get new treatments that might work out there available to patients.
Thermo - Thanks for your NWBO focused response
Thermo - Thanks for your contributions to the board. Just curious, do you and your group have other companies you are particularly interested In currently?
That is a pretty lame PR. It is just a link to the article.
Every major conference publishes abstracts of the talks and posters presented at the conference in a supplement to their journal. These are referred to as "published abstracts" - they are not at all the same as peer-reviewed journal articles published in the regular journal issues.
So from April - September 2022 they have been paying consultants for help in preparing documents for DCVAX regulatory approval. That is what I wanted to hear.
I agree - Decision making in the real world where insurance is involved is often idiotic.
Ok. FWIW - I am a senior researcher at a major medical center by profession. I do NIH-funded research studies, including clinical trials. I typically do my own statistical analyses for my studies. I am not a CVD subject matter expert but can certainly interpret results of studies including mechanistic findings. I think the studies of V to date clearly support EPA as the mechanism of action for CV risk reduction, and I do not think the R-It results are invalid. There is no scientific reason why V should not be approved and reimbursed for CV risk reduction here, in Europe, and elsewhere. Economic and political reasons are another matter. Regarding the stock, I am still waiting for the Hail Mary (Denner actions) to be completed.
Got it - I was thinking of the Japanese dietary differences and higher background EPA. In a sense, even the controls got more EPA (from diet) than patients in REDUCE-It.
Not sure what your point is, but if events rarely occur in a population (e.g., because they are lower risk to begin with), it takes longer to show a drug works to prevent events.
What Raf said...
FWIW - It is arbitrary. A famous biostatistician (Frank Harrell) told me once that the only reason p<.05 was chose as the cutoff for statistical significance had to do with a well-known early statistician who wrote a stats book and did not want to have to pay royalties to re-use previously published significance tables. So, he just created his own table that only included one p value level (p of .05).
Kiwi - It is not that it takes 4 years for EPA to work. It is that it takes 4 years for enough events to occur that allow you to see that it works in this particular population. Higher risk populations will show more rapid benefits. RRR will likely be bigger at higher EPA doses and in non-Asian samples. The RESPECT results are mechanistically compelling to a scientist - the marginal significance of the primary outcome is irrelevant in terms of supporting REDUCE-IT findings. It is the effect size that matters and the clear link between EPA levels and CV benefits. Assuming Germany has scientists evaluating supporting literature as part of their decision making process, I would think this new study would help.
Thanks - I had not seen that. It is a plenary session, which means the conference thinks it is a big deal and wants everyone to attend (no competing talks).
The company could with some journals announce the paper as "accepted for publication" once this happens, even before any actual publication is available to release. No idea if they would do this. If they wait for publication release to announce it, the timeline will vary by journal. Some journals within just a few weeks of acceptance will get the article listed on PubMed and will make the accepted pdf manuscript (not yet typeset) available on the government public-access website (this happens with studies that have been supported by NIH funding of investigators, which could be the case here). Other journals I have dealt with are quite slow, and you have to get the article typeset at the publisher and go through proofing by the authors before they make anything available on PubMed. NEJM often wants to announce their articles in a PR so the journal mandates keeping everything secret until they are ready to announce publication in a PR. Bottom line is it could get accepted any day and we still might not hear anything publicly for a couple of months. Just no way to know what's going on behind the scenes.
Fireman - I agree that it could still be a while. However, I can tell you from personal experience that 3-4 months would be more the norm, and that is only if you take a couple of months to do requested revisions. Most good journals now do reviews pretty quickly. All journals I review for these days ask reviewers to get back comments within 2 weeks. A lot of this depends on how fast Liau and company can revise the paper.
Don't know about others, but I assumed that publication had been submitted back in mid-May. New info suggests they were still doing analyses (sub-analyses beyond the basic TLD already reported?) until fairly recently, but that it has now already been submitted. Now the publication clock is based on info from the authors rather than assumptions. Whatever the reason for the delay in submitting, we are working our way towards actual publication "in coming weeks" (I hate that phrase but it is accurate). Just a matter of time now. It will get published, 100%.
No - If it was submitted two months ago, we literally could find out about acceptance any day. While there are exceptions, most good journals try to get decisions back to authors within a few weeks. Taking care of required revisions is the only thing that could slow it down, but I think even 6 months is pessimistic. I am actually happy that they haven't been trying to get this published for the past year - lack of acceptance after that long would be a very bad sign.
Thanks ES - Very well thought out post that summarizes the situation perfectly.