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Something still doesn't jibe though Pyrrhonian.
"Average per patient cost for P2 or P3 are nearly the same ($40k vs $42k): "
Ok. I looked at it that way for IMUC this morning. Allowed the same cost per patient per trial, regardless of the trial. Very similar patient care requirements. Still, what I came up with was $306K/patient if you include all money every spent by the company. That includes all R&D, salaries... everything. So it should be high, but 7.5 X the $41K you are citing?
The other direction in which this does not add up is in the rule of thumb of a $Billion to bring a drug all the way through to market. I assume that model includes all expenses by the company from day 1. As if they only developed one drug and brought it to market.
You give a range of 200 to over 5000 patients for a phase 3. Call the typical, then 1000. $1B/1000 = $1M/patient typical.
Comparing this $1M/patient to your $41K/patient is apples and oranges. But in this case, they are both fruit. They should cost the same order of magnitude. A phase 3 cost should dominate, or at least account for... say 40% of a company's total expenses bringing a drug to market. Yet $41K/40% is just $102K, not $1M. That is an order of magnitude discrepancy. Something is wrong.
(Not with Northwest in this case, with these two rules of thumb)
(Oh... and Pyrrhonian... I mispoke about a = b in that example earlier. b= 1. Not that it mattered.)
I will look at the reference(s). I stumbled on a similar paper this morning and tagged it. Scandanavian. I will take a look at that paper also in this context. It mentioned this effect of becoming a suppressor (for the antigen consumed?). Scary stuff.
I just hope you are wrong that a large percentage of the DC's that reach the lymph nodes are not proper presenters, or worse.
It makes sense that immature DC's would get eaten. The usual means of avoiding the macrophages may be as simple as outrunning them. The mature DC's are fast, right? I'm pretty sure macrophages are slow, even on the scale of interest.
I am going in circles on the trial cost issues. Thanks for the input. I think circles is better than not going at all. Sometimes it eventually leads somewhere in spite of the apparent futility.
But Northwest's expenditures are very large even considering some of the new info you provided. The total of $660M spent to date is not large according to your source... it is when you go into per patient detail that it seems way off. While the discrepancy is much larger for Northwest than other companies I quickly looked at, there is a large discrepancy for those other companies also. Something is ascue between a rule-of-thumb $1B to put a drug through trials, and a rule-of-thumb $50K to put a patient through a phase 3, but the site bring-up and maintenance costs stated in your article(s) do not fill the gap.
Very interesting about the efforts to simplify and unify the site selection and qualification procedure. Good stuff. We need lots more such good stuff. Too much chaos.
Yeah, that's true. It shouldn't grow forever, just until fully randomized.
But are you attributing general expense to the cost of randomizing new patients? Maybe not. I know you addressed this clearly yesterday, but I don't have a perfect memory...
If phase 3 trial costs are exponential as the trial progresses, as I believe they are reputed to be, then that would be because the ongoing patient care costs dominate the picture. And if that is the case, a smaller and smaller percentage of newly injected money actually goes toward randomization as the trial progresses.
I'm not claiming that the magnitude of expenses are making sense, just that they should be expected to increase as the trial progresses.
Pyrrhonian: Not sure which post to reply to... so not a reply:
One possible trap in the type of analysis you are doing, in my opinion, would be illustrated if you went through the following thought process... (thought I saw that you did this earlier today, but not finding it right now, so will just post the general idea.)
If you were to say that Northwest's methods for training the DC's is inefficient, resulting in a low percentage of healthy DC's that are programmed for antigen and in travel mode...
and then say that intradermal injection of the DC's results in a large percentage being eaten by phagocytes... then you could be faking yourself out.
If the body goes after DC's after intradermal injection, then it must be DC's that are not healthy or activated. An activated DC in travel mode would almost certainly have some kind of flag or cytokine signal that protects it from inflammation, if it needs one.
So instead of the stats allowing only a X b percent through (where a and b are small numbers), it would actually be a or b with a being equal to b.
That is a huge potential end difference in the model of stats of efficacy.
That is just one example of how you could be tricking yourself.
I just had a moment of clarity... like Jim on "Taxi".
They decided they can't or don't want to pay for a full trial for DCVax-L, in part due to the higher than expected trial costs, and in part due to DCVax-Direct being so good, so they modified the trial to be able to increase the odds of AA, with a confirmatory being the only way they intend to complete the trial.
Thus it is, in-fact, win or go home in the near future.
Can't say I have a guess for which way it will go... nor why the trial costs are sooo high, but I fear it is not theavery. But perhaps my fears will prove unfounded!
So, I hope that clears things up for everybody. No reason for any one to post any further. Just get your tickets at the window, or maybe you can sell any extra's on Craigslist. Post-time is apparently end of February. Well, technically, post time was a decade or so ago... but the race ends in a couple months.
Maybe a continued debate on how many tickets to buy would be in order. Just heed myself and others that you only have two months or less to place your bets.
I am not going to forget the Phase V crowd going after John. Even if they proved out right and LP has all the money in her mattress, and DCVax-L shows no efficacy, John is an exceptional person and for those types... those super aggressive, pretentious, greedy fks to go after someone like that is worth remembering. Not that there is much that I can do about it. But I will not forget.
John didn't pump Northwest. He cheerleaded a little bit, but that is good, if you believe in the products. And he believed in the products. He just pointed out articles of interest. He didn't push his opinion. And he actually didn't post that much. Kind of unbelievable that they would go after that type of person.
Maybe they realized he was a kind man. Not a vengeful man. Someone safe to attack.
Someday we are going to find out who those fkrs were, and some of us are not as kind as John.
Anybody else think it was strange how AF took every opportunity to mention how effective Provenge was? Like that is the thing to say to the immunotherapy crowd to get them to allow you to snuggle up. Like nobody here is going to remember him hammering Provenge and Dendrion repeatedly over the years.
Or was he perparing us for a possible early approval. Putting into our minds the failed Dendrion in spite of the approval of Provenge?
I have heard market cap valuations (NPV) for a drug upon approval as 4X expected annual sales, and 10X. I trust the 4X model.
So you are a stickler for accuracy? Are you French?
That would nake you a French stickler.
What's wrong with (a little) less than 50:50 cahnce on a 7 to 15 bagger mid-term, and possible 75 bagger longer term, at current valuation?
On trial costs. I tried to compare IMUC's total accumulated deficit to NWBO's in relation to number of patients through the trials.
NWBO has spent much more per patient than IMUC, though not the order of magnitude that would be suggested the way you analyzed it. Still a large difference.
Much of that (unspecified) difference is likely due to a substantially higher production cost because NWBO has to deal with the tumor. If DCVax-L does prove more effective / effective on a broader range of patients, then perhaps that will be worth it.
Further, Northwest had a huge number of patents. They may not own them at this point, but they did generate a huge number of patents and that needs to be accounted for when looking at total $ spent.
Further... Northwest did get drug across a recession. I am assuming this was more costly to them than to IMUC.
Further, if the formalities of a Phase 3 add significant per patient costs over a Phase 2, then that leans in Northwest's favor also. IMUC did not yet deal with a Phase 3.
So in the end... all these factors need to be taken into account before you can boil it down to the two that matter:
1) The larger per patient production cost for the vaccine.
2) The degree to which improper dealings added to costs.
I care far more about the first than the second, because the second is likely transient... at least with recent changes in staff.
I guess I give up trying to nail these things down with this overview approach. I tried to break it into cascaded factors... but that really doesn't make sense. Just have to wait for the results of the inquiry.
You don't get fever and chills from injecting insulin or compatible blood.
You don't get fever and chills from a flu shot due to the local inflammation. You get fever and chills from a flu shot because a non-self antigen has been introduced in large quantities throughout the body.
When you prick the skin you get inflammation that searches out bacteria, etc. You get a hightened local immune response. But heightened enough to destroy it's own DC's? Maybe, but that is certainly not a given, and certainly not similar to getting a flu shot.
There are probably a large number of DC's wandering around under the skin constantly. If the vast majority were eaten/destroyed by phagocytes, the immune system would not work. What alerts the immune system to go after these DC's that are processed into DCVax-L?
Assuming the relationship with Woodford does not get repaired in the near term.
The problem with that explanation is that the trial cost rises exponentially as it goes along.
To me, it makes no sense to suggest that at this point in the progress of the DCVax-L trials that there should be a radical change in leadership. Nor does it make sense to worry about reverting to a small amount of unfavorable financing, in a pinch... assuming this is a short term pinch.
The trial is too far along to worry about such things in my opionion.
In contrast, the things Pyrho is saying about the techicals of DCVax-L and about the overall financing scare the crap out of me. The financing issues I can research a little, and I will. First is to look at IMUC and other's total accumulated shareholder costs compared to his reported, super low per-patient trial costs.
Pyrho's technical analysis would take much more work to refute, and I'm not sure I have the noggin to handle that. But at some level I do understand what iwasadiver is saying in response. That you can have a lot of knowns forming a fairly vivid picture, but if you have enough un-knowns thrown in, then the dots may connect up, in the end, to form a very different, or different-enough picture. Immunology has an unknown number of such unknowns, and Northwest's trial has plenty in and of itself, as many have complained.
I should add that I know I need to look back over what some of the other longs arguing with Pyrho have said over the past months in response to his assertions. I am newly back and very much behind in that regard.
"$10mm - $15mm." There is one other possible explanation for LP's gross under-estimate of phase 3 trial costs for DCVax-L GBM.
Perhaps... during early work on cryo-preservation of the DC's and or tumors, LP accidentally fell into the liquid nitrogen cryo-bath. It took decades to retrieve her, but luckily that did eventually happen.
Upon recovery, after a very long restroom break, LP addressed the press with an update on the clinical trials. When she made the mistatement regarding the lower cost estimate for the GBM Ph 3 relative to Prostate, Les coughed and attempted to correct her, mumbling "BB BB BB", but Linda did not understand what he was saying, so braved on, embarrasing herself in front of the investment community that was familiar with modern trial costs. Apparently nobody has had the guts to point out her error.
"$10mm - $15mm." for the entire phase 3. That is certainly a tough one to explain. I guess a brain fart... that's all us LP lovers could say. Maybe half lie, half brain fart. But she should have addressed that by now.
Still, you have heard repeated statements over the years about drugs generally costing about $1B to get through trials. And a recent estimate of typical costs was about $1.6B even after correction by Carol of Fierce Biotech.
How do you rationalize coming down on NWBO for an accumulated total expense of $660M for all they have done at this point, including work on Ovarian, Prostate, and Direct?
Are their trial (patient) numbers so low compared to the typical that less than half the typical expenditure is excessive to the point of warranting bashing?
Maybe indirect for Phase V impact on recent funding SP then. Phase V inspired or forced Woodfords actions, and later prevented him from funding further, at least at a good valuation.
It doesn't make any sense to blame management for a 20% drop in SP in response to a 5% financing. That is transparently AF-like.
You say it is their fault because if they had explained the need for the financing, the shareholders would not have sold off?
Why would they have to explain the need for financing. It was right on schedule to fund the back end of a phase 3. I would agree that speculation about other uses for the money seems unfounded. Phase 3's are famously expensive particularly toward the end. All simple algebra said it was time to feed that beast of a phase 3. That simple.
"If everyone here thinks Linda is doing us a great favor by selling shares for $3.60, and think this is going to $225 then I might want to buy"
What are talking about here? The company has been pounded into submission by the phase V article and the aftermath. They have a hard time funding now, just as the authors intended. I don't see what is complicated about that.
I guess I don't know enough about the finance end to argue further. I might just add that some think the patent arrangement is a poison pill of sorts, and that many forms of poison pill put the shareholders in a position of having to trust management.
Even outside of poison pills, a company can get away with handing the retail shares over to the institutions using a death spiral contract. AEZS recently did that, and got away with it. Absolutely unbelievable that it is legal, but you can't get attorney's to contest such deals.
So every retail shareholder is in the position of having to trust the management. Many longs here trust LP out of gut. Time will tell if they are fools to do so, or if they have good guts.
At the current valuation I would agree that having company assets arranged to be unavailable as part of bankruptcy liquidation is concerning. But most longs are in at a substantially higher share price than the current one, so while the lack of a fallback of liquidating assets may not be insignificant to them, it is not a huge issue. They are going to lose their asss anyway if the company fails.
"They are past due. The holders can refuse to take payment."
Ok, now I am with you. If you said that before, sorry I missed it. That is pretty clever.
Not long ago it didn't seem possible that an unwanted group could accumulate majority shares. Maybe I didn't look at that carefully.
But particularly if you consider Woodford an allie, it didn't look possible to me. But... with Woodford on the defensive, and possibly unable to help with financing at this point, they could be vulnurable.
Talking all business about LP's plans and backups, I do not mean to imply that she is all business. The longs here all know that she lost a relative to cancer, I believe a stepchild, before her entry into the Oncology business space.
No way to know where the business interest ends and the humanitarian interest begins, but to a large extent, they align.
If LP thinks that the immunotherapies are the best long term approach to dealing with cancer, then they are also the best long term direction for the business end, whatever the short-term challenges.
The longs all know this. Just saying I know this.
But if there was a takeover, what would prevent the new majority shares from voting to pay off the loans for which the A patents were collateral?
LP's recent statements regarding reimbursement for Hospitatl Exemption patients in Germany was a little surprising to me. There is more delay suggested in her statements than I expected to hear. But I would point out:
1) She talks as if AA, for example, is not even a remote possibility, in the near term. Yet many consider it a possibility. It seems that there is no advantage to NWBO for her to talk about any such possibility in the near future. Or rather, a concern about the effect of a dissappointment may outweigh the immediate, very short term benefits of talking about the possibility.
2) In the past there was a great deal of debate about how far the trial must be along before reimbursement $ could be assessed. I would think that even if they could asses efficacy and corresponding $ now, the amount allowed would not be the central, most likely projected efficacy, but that less the relatively large uncertainty in the immature data at this point. If so, there is advantage to waiting for the data to mature beyond a simple go or no go. Even if the median PFS and or OS stays the same, the noise reduces as we go along, and thus the allowed reimbursement likely increases.
"I simply cannot understand how having the UK property not owned by the company benefits all the shareholders."
The complaint in Phase V was that NWBO did own the real estate when it should be Cognate.
Either way, the advantage to shareholders of NWBO is that owning that property increases the chance of approval of DCVax-L. Part of consideration for approval is whether the company demonstrates the ability to manufacture the product at the volume required to fullfill the role that would result from approval.
But no company is going to build a large enough facility prior to approval to produce the volume required after approval. That is not practical. The best they can do is show a manufacturing scheme that is scalable and the intent to scale. Buying the land shows the intent to scale.
I am not saying that is the only reason for LP to secure the land, I am just responding to your assertion that there is no benefit to NWBO shareholders. There is. It is the increase in the odds of approval of NWBO.
Clearly LP responded to the discovery of gold in them thar DC's by forming a gold mine and Sears Roebuck to provide picks, shovels, wheel-barrels, and Levi's. The gold mine is a potential blockbuster in it's own right, but everybody knows that the odds of failure for any given mine are high, whether there is gold in them thar hills or not. Sears Roebuck is the safe bet, and in the end, Sears Roebuck made more money than all the mines put together (or something like that). But that doesn't mean that LP's mine is a con. It was likely her best guess at where the gold was located, and hopefully there remain good odds for it's success.
The gold mine served as a gaurunteed customer for Sears Roebuck... but that does not reduce the odds of it's success.
He was right though Vator. It is win or go home for shareholders, even if you trust LP.
And one of the biggest elephants in the room is the lack of accounting for vaccine production costs. At best, the costs right now, at low volume and with limited automation, would probably be high enough to scare everyone. So not divulging it probably makes sense. But with no accounting of the costs whatsoever, it could be anything. It could be astronomical. Not knowing where the $'s to Cognate have gone... real estate? Training? With no accounting, the per vaccine production cost could be almost anything.
Again... if you trust LP et al... then maybe all is well, but good thing there is a special independant board member tasked to investigate. I am sure Woodford needs that production cost number also (if he doesn't have it). Again, the number will not be representative of actual cost when the ball gets rolling, but still, a number needs to be publicised.
Makes total sense, but does require trust. From that perspective / with that trust: Phase V was published to break down trust. AF was here to break-down trust.
That Phase V article is huge. But just into the first 5 pages or so, they seem to be alternating between saying that LP and Toucan are stealing (from NWBO) and hording vast wealth, and then saying that LP and Toucan have been too broke to pay bills. Which is it guys? Seems there many researchers did not speak to each other before compiling the article.
Not that I am not worried, but the more inconsistencies I read, the better I feel.
Kind of like AF's presence here. A powerful type, and intelligent, so a little scary as an adversary. But full of sht so often that you start to worry less and less about what he is saying.
I would agree with both of you that it looks deliberate and may not be part of any evil plot on the part of LP. Just survival if NWBO fails. But it is a little complicated and a little scary.
Is she just positioning for the possibility of failure, or does she know it is going to fail? I guess that is a key question.
Clearly there are people wanting NWBO to fail. Financing is being made difficult. To me, that plays into the picture of what LP is likely up to.
If DCVax-L fails, would shareholders stick around for DCVax-Direct to mature? Would they maintain SP enough to allow financing? I would think that they would after a dip. If NWBO could survive the dip out six months or a year, then they might get far enough along with Direct for shareholders to forget about DCVax-L. But with this aggression surpressing share price, it seems unlikely that NWBO could make it that long. So... that does drive the need to protect the patents, at least the DCVax-Direct patents. Many DC patents could relate to DCVax-Direct even though DCVax-Direct is relatively new.
Never mind. I found the article. I never did read the Phase V article. Now I will, keeping in mind the history of FUD against NWBO.
I missed the discussion about the patents being used as collateral for a loan. That is a huge issue.
The primary financing for quite a while has come from Woodford. Unless the loan was from him, why would he allow that without major objection?
Was Cognate the lender?
Is the loan repaid?
Is there firm record of the original deal and of the repayment?
Did Phase V dig this stuff up? Make this stuff up?
Actually, Flipper has been saying by end of February for a while now. Coincidentally, the financing will carry them to end of February,
at which point, if the good news in question comes, or any good news, the warrants will likely carry them another couple of months while they re-arrange everything.
Good Stuff ReadyForBlueSkys.
Sorry for being so aggressive a few posts ago. Of course a dip 2 days before Christmas is unsettling.
Re: Deleted post:
Not sure why the post was deleted. It is about Celldex, but there was an era where NW was compared to Celldex often. It was an important part of the history of trying to fund development.
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Back in March of 2014 when I looked at this issue, the Celldex site said,
"EGFRvIII is expressed in tumors in about 30% of glioblastoma patients. It has not been detected at a significant level in normal tissues; therefore, targeting of this tumor-specific molecule is not likely to impact healthy tissues.
Rindopepimut is administered via intradermal injection and consists of the EGFRvIII-specific peptide sequence conjugated to the carrier protein Keyhole Limpet Hemocyanin (KLH). Rindopepimut stimulates the patient’s immune system, inducing pronounced EGFRvIII-specific humoral and cellular responses. 85% of patients in clinical trials evaluating rindopepimut developed significant anti-EGFRvIII antibody titers, which increased with time on study. The majority (67%) of these patients developed titers above 1:12,800. Such immune responses may contribute to the direct destruction of tumor cells expressing EGFRvIII.
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If you unwound this properly, you had only 30% of GBM patients get through gate 1, 85% of those through gate 2, and 67% of those through gate 3. They dropped the patients that had titers below 1:12,800.
That means that only (.30)X(.85)X(.67) = 17% of patients actually made it all the way to the continue in the trial.
What I surmised at the time was that when they reported efficacy numbers, it was actually on this 17% of patients. It was a little bit ambigous as to whether they were referring to the 17% or 17%/.85 = 20%... but given the style of the presentation it seemed likely that they leaned all the way to talking only about the 17% that got full treatment.
I agree that the 17% would not be the intent-to-treat-population that the FDA would look at. But I was not talking about what the FDA would look at, I was talking about the numbers they PR'd and Cramer and or Feuerstein regurgitated.
Woodford's last funding came late. Everyone knew the $ would not last at the burn rate because it came late.
Big surprise: Fledgling biotech nearing the end of their first Phase 3 needs funds to continue. Shocker! WTF is going on here!
Big Surprise: Fledgling biotech has to fund at a low value because SP tanked after a flaming article with key contributions from an anonymous source.
"GSK has nothing to do with NWBO or DCVax."
You posted a quote from MD Anderson that says that Budzar had no conflict of interest with DCVax-Direct. I responded that they absolutely did have a conflict of interest due to a huge contract with GSK for a competing therapy. Note that the dates below are not ancient history. This was all happening about the same time that you and Budzar were maligning DCVax-Direct.
Here is a little bit more about GSK's aggressive and illegal practices in competition:
Business News | Fri Sep 19, 2014 9:45am EDT
http://www.reuters.com/article/us-gsk-china-idUSKBN0HE0TC20140919
"China fined GlaxoSmithKline Plc (GSK.L) a record 3 billion yuan ($489 million) on Friday for paying bribes to doctors to use its drugs,"
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The super lucrative collaboration between MDA and GSK was in the immunotherapy realm:
http://www.mdanderson.org/newsroom/news-releases/2014/collaboration-with-gsk.html
"MD Anderson News Release 04/08/14
The University of Texas MD Anderson Cancer Center announced today it formed a research alliance with GlaxoSmithKline (GSK), a global leader in pharmaceutical development, to strengthen its efforts in advancing therapies that train the body’s immune system to combat cancer.
The collaboration completes an ambitious plan to partner with leading pharmaceutical companies to more rapidly develop cancer immunotherapies as part of MD Anderson’s Moon Shots Program. Through this venture, GSK and MD Anderson will work together to identify new therapeutic approaches, evaluate patient responses in clinical trials and use those insights to develop immunotherapy drugs."
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http://www.bioworld.com/content/md-anderson-gsk-ink-potential-335m-oncology-drug-pact-0
"Houston-based MD Anderson granted GSK exclusive worldwide rights to develop and commercialize the antibodies, which activate OX40 on the surface of T cells, in a deal potentially valued at more than $335 million. London-based GSK will make an undisclosed up-front license payment, fund research collaboration activities at MD Anderson's Institute for Applied Cancer Science (IACS) and provide payments for reaching development, regulatory and commercial milestones. MD Anderson also will be entitled to royalties from the commercial sales of products developed under the collaboration."