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"A total of 2,986 patients from 30 studies were included in the meta-analysis. In all, the frequency of MGMT promoter methylation was 44.27 %. -- www.ncbi.nlm.nih.gov/pubmed/23397067
Pseudoprogression was recorded in 21 (91%) of 23 methylated MGMT promoter.... MGMT status (P = .001) and pseudoprogressor detection (P = .045) significantly influenced survival when [standard of care was used.] -- www.ncbi.nlm.nih.gov/pubmed/18445844"
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44.27% X 91% = 40.3% of patient population likely to be pseudoprogressives.
If general population recruited fits this 40.3% pseudoprogressives, then how many pseudopgressives so far placed in
1) main trial +
2) pseudoprogressive group
3) information group
1) 300 patients
2) 32 patients
3) About 50 patients
Total about 382 patients of which 40.3% expected pseudoprogressive. That's 154 pseudoprogressors to be accounted for.
Didn't the pseudoprogressive arm get created relatively late in the trial so that many pseudoprogressives were possibly included in the main trial early on? Or no... the pseudoprogressive group was there from the beginning, or at least after phase 2.
Still, 154 pseudoprogressors to be accounted for between the main trial, the pseudoprogressive group and the information group? Apparently not, but why not?
What is wrong with this view?
382 patients went to 1 of the above 3 groups and 154 were likely pseudoprogressors. No?
I thought 45% Methylated MGMT of which 91% will be pseudoprogressives. That's about 41% of the patient population being pseudoprogressives.
I am wayyyyyyy off. What is my error here?
A lot of pseudoprogressives in the trial... what the need for a pseudoprogressive group?
It would allow a look at performance in that subgroup without unblinding the main trial... right?
But weren't they / didn't they unblind the trial for an efficacy look anyway at the last interim? If not, then things make more sense to me. Ie if they only unblinded the pseudoprogressive group.
Actually... 40% pseudopgrossevives X (300 in main trial + 32 in pseudoprogressive group + 50 in information arm (50?)) = .4 X 382 = 153 pseudoprogressives with only 32 in the pseudoprogressive group. So... 121 pseudoprogressives in the regular trial or the indeterminate information group.
Why so few (32) pseudoprogressives in the pseudoprogressive group? Of 300 enrolled, shouldn't there be about 120 pseudoprogressives? Does that mean about 88 are elsewhere? Ie mostly in the trial with some in the indeterminate information group? Is this due to the pseudoprogressive group being formed late in the trial or some other reason?
Almost certainly rehashing things you and others have covered in the past, including the recent past... my apologies if so.
Flipper: If the pseudoprogressives were setup without a placebo, then it was agreed up front that they would be evaluated relative to historical norms, right? There is no need to wait for X events, right? And statistical significance(s) is(are) not all created equal. Ie... if the data is so good prior to full statistical significance that it is a little scary to think of the number of patients denied the treatment, then statistical significance becomes a confirmatory... right? Isn't that the gist of the supposed new attitude by the FDA?
Is the MGMT Methylation status usually the same for the tumor and the rest of the patient's cells?
If so, then maybe DCVax-L will get early approval for all Methylated MGMT patients rather than just all pseudoprogressives. Not a big difference in numbers if 91% of Methylated MGMT patients become pseudoprogressors, but it would simplify the process to be able to just test that status for the patient, possibly even prior to surgery, to determine if they are a candidate.
Prescribing (generic) Temador to all Methylated MGMT patients would probably make a lot of sense. Even if the 9% would not benefit... at least there was a 91% chance apriori that they would.
Of course such an early approval in no way precludes approval for all patients once the trial runs it's course. And you guys may have provided good arguments for why early approval for all patients is likely... hard to follow for me I must admit. But the idea of early approval for the pseudoprogressors or possibly all Methylated MGMT patients is much easier to see. Even to me, seems a no brainer.
Hey... I am a physics guy... sort of. Very different from bio / biochem.
Did you get this UC Irvine change out on Yahoo? I know it's difficult to post links on Yahoo, but might be worth the effort to distribute this further. NW dropped much more than most small biotechs today. It seems possible this issue contributed.
I will post it if you want.
I take full responsibility for the XBI drop today. I was out, waiting anxiously for my powder to dry, then went all-in from 10:06AM till 10:45AM.
The Clinton Tweet was at 10:56AM.
I know from experience that my actions caused the tweet. I am very sorry.
Might you conclude that the indeterminate arm is 40% pseudos? (0r 38%...)
It's fuzzy but that does sound right. Did the FDA go along with that? I remember a debate about whether the trials could differ.
Someone recently posted that biotech companies are somewhat vulnurable during certain periods of communication with the regulatory agencies. A related issue, also mentioned, was the potential effect on patients and potential future patients that negative speculative posts can have.
Belatedly the wisdom of that post or posts is sinking in. So I want to be very clear about at least one thing:
The information arm data clearly indicates efficacy for DCVax-L for a broad range of patients including true early progressors. The true early progressors are almost certainly not in the subset that has a strong response to Temador.
Not that anyone will remember who posted what... but maybe one or two patients.
Regarding the lack of a functioning SEC: Offtopic... I don't think so. NW has been under fire a lot by people like AF for many years. Every six months or so investors get hyped about trying to do something about it, and complain to the SEC.
I guess Deep Capture and or a related organization is finally doing something.. . does have a federal action going, but the topic will come up again.
To understand the SEC you have to review the videos of Cramer talking about his hedge funds illegal actions during a publicly aired video on "The Street". After, people complained to the SEC, an action against Cramer was started. Then, without good explanation, the action was shut down. In the infamous videos Cramer explains the need to have access to an insider at CNBC in order to manipulate investors. I believe this was just before he got his daily show on CNBC. The irony of this should be infuriating. Unbelievable.
So that is where to begin to see the SEC as ruled by who has what on whom. Cramer had something on somebody(s). I think that is clear.
But maybe that was in the past?
So what about this recent death spiral deal at AEZS? A month ago, AEZS, a small cap biotech listed on the NASDAQ made a very special deal with investors that will destroy the holders of the float. But they hid the deal . First not mentioning it in their summary PR's, nor even their summary SEC filings, but second, writing out the deal in a deliberately convoluted way that would take most investors weeks to unravel. And it did.
This was the new deal for now magic B warrants that had already been issued.
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which would permit such Series B Warrant holder to obtain a number of common shares equal to 200% of (i) the total number of common shares with respect to which the Series B Warrant is then being exercised multiplied by (ii) 0.81 divided by (iii) 85% of the quotient of (A) the sum of the VWAP of the common share for each of the five lowest trading days during the fifteen trading day period ending on and including the trading day immediately prior to the applicable Exercise Date, divided by (B) five, less (iv) the total number of common shares with respect to which the Series B Warrant is then being exercised.
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This is called a death spiral. The farther the share price goes down, the greater the number of shares a B warrant is worth. There is no way to know up front what the dilution will be.
When you scrutinize it, many of the layers of this deception have no meaning whatsoever. So it is clearly a deliberate effort to hide the real deal from the retail investors. But they are legally required to communicate any deals to the investors. How then could it be legal to deliberately confuse things? And further, the units aren't even right. If you do make an assumption or two and unravel the garbage, and calculate the moving number of shares per B warrant, then number comes out to units of 1/$. That can't be right.
In the end, the deal is:
For every B warrant, for the price of 62 cents, the holder can receive:
$2.287/(RSP) shares of commons stock, where RSP is a low ball estimate of the recent share price.
For example, at the current price of 5 cents per share, a B warrant holder can receive $2.287/$.05 = 45 shares of common stock for 62 cents, paying 1.4 cents per share.
***************************************************************************
There were hounds that shouted out this deception by the foxes, but few listened. It took weeks for it to become widely known that this was a con job. But the friends and family of the insiders would have been provided, on day 1, this equation (B Warrant + 62 Cents = $2.287/RSP Shares) not the convoluted conjob that the retail investors who read through multiple SEC listings and all their attachments eventually uncovered.
Where is the SEC? They can't act. The rank and file SEC workers reportedly spend an unusual amount of time downloading porn... which opens them to blackmail, so they have their hands tied... . It works out perfectly. It is all about who has what on whom.
Yes, when they become desperate. Cramer openly described the tactics used at his Hedge fund in that situation. That is the scary part.
The general idea of shorting is not unreasonable. It makes sense, particularly in small cap biotech where pumping is needed prior to funding rounds.
But... the stats are so bad on small biotech failures... ie failure rate so high, that it emboldens massive shorting across the board on small cap biotechs. The only problem is, once in a while a small cap biotech proves out and becomes a 10 or 31 or 100 bagger. So if you had leveraged your short bet on such a biotech 300 fold... a number I vaguely remember as often real... then you are absolutely fd if such happens quickly; so they lie and cheat as they scramble for cover. Again, Cramer publicly described this common practice.
To me, it is like many similar phenomenon that I have witnessed in my life. These hedge funds get to gauruntee success with the above practices. And it is tolerated, because those funds represent big big $. And people from big big $ land have the right to big big $. And if you are not from big, big $ land, then you have no rights to $. That is the law of the land, in more than trading.
So that is why the information arm is not symmetric. The missing pseudo-progressor category was made a seperate arm and kept blinded... If I used to know that I forgot in my absence.
Thanks Flipper.
Hmmmmmmmmmmm
Have to think about the implications and possibilities. If they can identify future pseudo-progressors, and if the pseudo-progressors in the trial are all doing very very well, then it would be unethical to withold DCVax-L from those apriori identified patients... maybe? (ie future pseudo-progressors outside of the trial... ie from the whole planet... starting with Germany)
I think that Smithonstocks may have inadvertantly added to the confusion. If you are long, he is an ally... but he writes a lot, and eventually he is bound to be off a tad. I think that is the case here.
Smithonstocks 9/8/2015:
http://smithonstocks.com/northwest-biotherapeutics-thoughts-on-suspension-of-screening-of-new-patients-in-the-phase-3-dcvax-l-trial/
First line of the last paragraph in the article:
"In all three of these scenarios, I am uncertain as to why the regulators are requesting information while the trial is ongoing."
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But NW PR didn't say that regulators had requested the information.
Reviewing NW's only two statements on the issue as far as I know. Both in their PR 8/21/15:
http://www.nwbio.com/nw-bio-confirms-phase-iii-trial-of-dcvax-l-for-gbm-brain-cancer-is-ongoing/
"The only change in status of the trial is that new screening of patient candidates for the trial has been temporarily suspended while the Company submits certain information from the trial for regulatory review."
"The Company is in the process of preparing the trial information for regulatory review and anticipates submission within the next couple of weeks."
32 pseudo progressors.... seperate and apart from the "information arm"?
I just read a little bit about the VW takeover attempt. It is pretty interesting. Did not get to the end yet. The story surprises me because a Porche owner told me 40 years ago that Porche motors were higher precision (balanced and blue-printed) VW motors, so I have always assumed the companies were really one. I guess not.
Flipper: "The separately analyzed 32 patient pseudo progression arm:"
Are you talking about patients in the information arm or outside of the information arm? Who are these 32 pseudo-progressors? In the trial, or outside like the information arm?
Schnauzer: "VW went to almost $1,000".
I have heard this referenced a couple of times now, but I don't know what you are talking about, and can't find it on quick web searches. You are talking about a biotech VW?
"If you do a little research on combination chemotherapy-immunotherapy, you will find that the current SoC is actually synergistic with DCVax-L. Temozolomide is particularly enhancing for immunotherapy, if each are administered at correct intervals. This is because, among other beneficial synergistic effects, temozolomide induces lymphopenia/lymphodepletion. NWBO and Linda Liau are very aware of this.
I still hold out that the screening stop is for something positive.
I have now depleted my one post for today...GLTAL and patients."
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Yes, I talked about that synergy in a post yesterday. I have seen Linda Lau's presentation of the phase 1 data where Temador (now a generic, so should call it "Temozolomide" but a pain to remember because I no longer post here often enough) saves the day.
However, if you research things a little, you will find that Temador does not help everyone, just a subgroup. It is not synergistic for everyone, just helpful enough for that subgroup to shift the overall stats. Yet they prescribe it for everyone even though at some point it begins to damage the immune system. You do some research. I dug that stuff up two years ago when I first started posting here.
I had reprinted one of her messages before I realized it could be a problem. People do it all the time on this board. Probably best to paraphrase if anything, not cut and paste, no quotes.
For sensitive stuff, telephone is best. Feasible deniability. He said she said.
Your actually not supposed to reprint her written replies. You actually agreed to such in the correspondence if you read it.
I think you get slotted for phone communications only if you violate that agreement and they are made aware of it. So, you can probaby still talk to her on the phone.
I agree that it would be a stretch, at best, to call a change to healthier patients (for Direct) a new or different method. However;
1) Total assumption that this is what they were talking about A/B.
2) Healthier patients would probably be a more realistic test for how Direct therapy would perform if approved and implemented, and therefore a better test. If approved, patients would typically start getting Direct while they are still able function in a minimal way, which is the threshold(s) you listed.
Maybe NW was too ambitous trying to deal with patients that were too far gone. If so... that is the purpose of a phase 1, to find the limits. Further, the patients that were beyond the points you describe are more likely to have severely damaged immune systems because they are more likely to have been given very large levels of chemo and radiation as a last resort. Probably the right thing to do, if you are not anticipating a last ditch immunotherapy.
If the screening changes were checking to see whether SOC had destroyed the immune system, then I think that is a legitimate change. Not sure because I did not understand the recent post on that topic. But if so, if those were markers referenced, then that would be legitimate.
If Direct proves out, as it appears to be doing, then SOC will likely need to coordinate itself with this new therapy. Radiation and chemo can both damage the immune system. I think, surprisingly, radiation even more than chemo. But I am sure that depends on the details.
The health of the immune system needs to be monitored and used as feedback as radiation and chemo move forward... if an immunotherapy is to follow. And on the average the amount of the combination will need to decrease to get the best effect of the combination of all three therapies. That is a near certainty.
Thanks for the post of information arm data. I had been critical of the presentation of that data, but looks like I did not look carefully enough.
I don't know. I really think they should wait till Tuesday for any big PR's. Wait until the market jitters shake out and ... my powder drys out.
In fact, nobody likes Mondays. That is a horrible day for national Alzheimer's day. They should move it to Tuesday this year.
Regarding rigid FDA protocol. Supposedly these policies have changed / are changing. But as I understood them a couple of years ago, you could have the following scenario's. This is nostalgia for Flipper et al with a new example that I thought was entertaining:
Someone runs clinicals on cooling the hypothalamus 10 deg C (or whatever part of the brain it is they cool to reduce metabolism) during recovery from a stroke. The clinicals prove out the concept and the treatment is approved and becomes standard of care.
Someone else sees even better results when they heat the hypothalamus 10 deg C, in animal studies. So they work on the human trial design with the FDA, and this is what they come up with. The patients must be provided SOC along with the experimental therapy, so the regimen will be to do nothing at all and then analyze the results.
Here is a better hypothetical one:
Researchers find that some forms of epilepsy do not respond to treatment and endanger the patients lives. They find that removal of the left hemisphere of the cortex stops all seizures yet the patient is functional. Clinicals prove this out, and this becomes standard of care for these very difficult cases.
Later researchers find that removal of the right cortex is just as effective and has less side effects. To prove this out the trial plan is to first perform SOC, then remove the the right hemishpere.
Here is an even better one:
Researchers find a chemotherapy that slows GBM for about 35% of the patients. It is found that the chemotherapy must be dosed properly because high doses destroy the immune system. An optimal dose is found for increasing the Overall Survival for the broad population. This optimum dose is a balance between damage to the cancer an damage to the immune system. Since it does improve OS for the broad population by a whopping 2 months, it is approved for all patients with GBM even though it only helps 35% of them and hinders all of them by damaging their immune systems to various degrees. Not enough damage to outweigh the gain for the lucky 35%, but significant damage.
Along comes an immunotherapy for GBM. It is found that the SOC chemotherapy is statistically synegystic with the new therapy for the broader population... good thing, because the FDA requires application of SOC... and if not, there will be a war if you try to shut it down with an army of AF's and similar ilk wielding pens full of poison.
So in the trials for the new immunotherapy for GBM you require a known immune system toxin to be administered to previously determined (before the immunotherapy came into play) optimum levels, indiscriminately, before administering the immunotherapy. WTF!
Not entirely true that you can't look backwards. You can, and you must.
I am not blaming the FDA here. I did not say they are in the way. I said that NW should have that information arm under a genetic microsope. They probably do, but if they don't, it seems a tremendous waste of an opportunity.
If you have followed any of the cases of desperate people with GBM online, and listened to the details, and gotten pulled in emotionally... I did. A very sad case that I don't to talk about... but it pulled me in close enough to cut through all the BS and realize the obsurdity that this patient had not had any genetic analysis. You look at every one of the available therapies, except DCVax and one other therapy, and they are all genetic specific. Even DCVax is genetic specific regarding whether or not Temador is a useful adjunct.
There is a ton of knowledge at this point about which drugs/therapies work for which genetics, yet I don't think that is current standard to do a complete genetic analysis on a patient ASAP. Blood tests before tumor removal, and analysis of the tumor afterwards, before deciding which therapies to use. Things are moving that direction... but this is solid known stuff. It makes no sense to spend a couple decades moving that direction. Ridiculous. That I do blame on the FDA.
At this point, it seems to me, that they should be able to look at the genetics of the people in the information arm and understand to a large extent why some are true early progressors and some are pseudo-progressors. With that info they should be able to analyze those two groups separately. Couldn't that lead to an early approval for some subgroup? If response is overwhelming then the FDA is supposed to get off it's arsh and forego some of the usual formalities.
On the other hand... they could package the good data better. They could give more specifics on the likelyhood of those direct patients (all but 2) continuing to live 6 more months. They could deliniate true early and pseudo progressors and clarify that issue rather than pretend they are all true early progressors like Linday does, which smacks of... They could at least address that issue/question.
The same data could be presented in a more meaninful, and thus more pursuasive way. And since it is by Bosch and people from MD Anderson... that would be a much stronger punch.
If it does go down that way then it would be legal, but would it be fair that it was not simulcast?
The presentation window runs till 8:45PM EST, so he could present new info after after-hours trading ends at 8PM EST. (But not before that time since no webcast.) However... why would they present new data here and not in London?
"Dr. Bosch will discuss new and emerging information from the Phase I trial of DCVax-Direct in regard to ongoing patient survival and factors associated with such survival. The poster is entitled “Cytokine Production by Human Dendritic Cells When Administered Intratumorally Correlates with Clinical Outcome in Subjects with Advanced Cancers.” This poster presentation will be presented in the 6:45 to 8:45 pm (EDT) Session A on Wednesday, September 16, 2015."
No, not really prospecting, but I am trying to grow gold. Couple of gold nugget starters in a bucket. Candlelight. Tried playing Barry White, but it only seemed to excite one nugget. The other one acted insecure, inadequate? So then I tried little headphones. I play Barry White for one nugget, and Kicky Dee for the other... that seems to work great!
That and even smaller cap biotech gambles. I am just north of paying rent and my own business development. Slowly coming back.
Thank you sentiment. I was out mining gold to buy NW stock. But if I sit out while it triples, it will take three times the gold to get back in.
Cramer is associated with lots of big pharma investment by lots of very wealthy people. Cramer invented AF as a biotech reporter. That's a fact. AF has been on the warpath against Northwest for years. That is a fact.
Maybe you are right, but I have always thought that Yahoo has enough readership to effect trading for small cap biotechs. NWBO might not be super small cap any more, but it is still relatively smallcap. And it wasn't long ago that it was very small cap. Flipper was around in that era / since that era.
You don't have to be such an arshlo, as the germans would say.
Sorry Captain, but.... If this is about full enrollment, then recall that reimbursement relating to the German Hospital exemption may be gated by full enrollment. That would be a big deal. Full enrollment means stopping the exponential growth in trial cost, and reimbursement would... well it would be income.
That line of thinking has probably been on the board twenty times in the last week... sorry if so.
There were arguments that the reimbursement would not hinge on full enrollment. Perhaps good arguments... but I think it does, and I think that might be part of the news tomorrow.
That or pseudo-progressives...
My post wasn't very clear. Hope you did not misunderstand me. I just think there is a chance that the big enrollment mystery involves that early progressive group that you have talked about so much.
You may have brought arguments in that direction over the past week. I have not been reading the board much until today. But I didn't see anything along those lines today.
My details about that situation are a mess I'm sure. I can almost feel your face contort reading them... I do that to people.
Being broke is a good motivation to find an angle to call enrollment complete. It also provides good motivation to get early approval on some cohort.
I thought I would hear Flipper talking about early approval for the early progressor arm. But that's not really an arm I guess. Not really part of the trial.
You only get jail time if the $ amounts are relatively small, and or you have a chance to beat a Bush in the next presidential run.