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Not so. I don't see anything from he who shall not be named again. He is probably working on it. Or his masters are probably working on it... but so far they got notin it would appear.
Note to self: In the future, when you hear that he has masters... don't assume it is a typo or an incomplete phrase regarding educational credentials.
Key Q? Hold lifted? What exactly does that mean?
"On Friday the partial clinical hold was lifted by FDA"
The hold was on screening patients, right? What is the significance of removing the hold at this point, past PFS target number of events threshold?
Were the provisions of the hold that screening stop until they reach that target at which point screening would stop anyway?
No... screening would have stopped relative to reaching the original enrollment target. Not a function of events...
But I believe that the whales will be scrutinizing this statement. I think that the clinical hold was a huge factor in dropping the price. Not saying the largest, but it was up there. So if the lifting of the hold is real, and as significant as one might infer, then SP recovery here, with no further news should be substantial. But whales become whales by not biting on hooks out of reflex. They study the news. AF will claim the lift means nothing. Smith will likely have an accurate interpretation, but will they trust Smith? Who will they trust?
Coca Cola was originally sold with Cocaine in it. Then they went to something a little more tame, ie caffeine. It seems a good bet that Coca Cola pushes more caffeine than all the Starbucks and Pete's Coffee houses combined.
A logical progression would be from a narcotic, to a legal drug, to a drug that is actually good for you, and makes you feel good at the same time.
Anavex 2-73 is the answer. Taste the Feeling!
One more very good reason to be careful what she PR's about the DCVax-L trial. (yes I can find a silver lining around any clouds over my pet stock and cancer cure, at this point)
I hope you are right. But lets say it falls short of median PFS (or OS for that matter) target. Didn't some if not most of the checkpoint modulators get approved off of great results for very much less than half the population so that their median improvement in efficacy was zilch?
That old question about the median being the measure of efficacy, and how that reflects no efficacy if there is no efficacy in more than half the population.
Yeah; for some time I have thought that was likely part of their strategy. Looks like it may be unfolding that way.
As a GBM patient, or friend or relative thereof, I would sure be angry if a new GBM therapy with good efficacy was (pre/conditionally) approved in the UK, and I had to fly all the way over there to get treated because it was not approved in the USA / Canada!
That all sounded just perfect! I hope he gets the role! Good post!
DCVax-L sure fits right into his description!
Maybe if LP is really NICE she will give it away at production cost!
Sorry Flipper... I have to entertain myself with such dark jabs.
Here's the thing. The link Highwayman provided regarding the review policy says they can only use public data. But later it says that the sponsor must agree to allow the reviewers to request data from the regulatory agencies if they need further data.
So... none of it makes any sense to me. I want to believe you... and the listing is real, but what could explain these discrepancies?
Maybe they were scheduled to go under review, but the data was not available on time. Or maybe they signed up for the review before they had the data, and later decided not to go forward with the review.
Or.... ????
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https://www.nice.org.uk/process/pmg24/chapter/instructions-for-companies
“To ensure that the appraisal process is as transparent as possible, NICE considers that evidence on which the Appraisal Committee's decisions are based should be publicly available.
NICE requires the medical director of the company to sign a statement confirming that all clinical trial data necessary to address the remit and scope of the technology appraisal as issued by the Department of Health and NICE, within the company's or any of its associated companies' possession, custody, or control in the UK, or elsewhere in the world, have been disclosed.”
"NICE requires companies to consent to it being provided directly by European Economic Area regulatory authorities all clinical trial data necessary to address the remit and scope of the technology appraisal as issued by the Department of Health and NICE. NICE will only ask regulatory authorities directly after having first approached the company for the information and the company is unable or unwilling to provide the information in a timely manner."
"He can not confirm that NWBO has elected PD-1" PD-1 vs the complement PD-L1?
I hope that the alleged Parkinsons Phase 2 with a Placebo leg is real. Exciting stuff.
;) While I understand how you feel, and understand how things look, I would point out that through all of this there has always been a feasible explanation for all apparent problems. Given the valuation and potential valuation, for me I think it is worth the risk. Cheer up!
I agree about the improvement in sleep being a huge benefit for caregivers, which is very important. I would add that not only does improved sleep also improve quality of life for the patients, both at night and during the day, there is a process for expelling mis-folded proteins from the cell that only occurs during a certain period of sleep. I wish I knew more about that. What I do know is that researchers have reported that at some point during sleep the brain cells contract dramatically, increasing the space between cells, then vibrate. This is believed to be a mechanism to expel large molecule waste that can't be broken down. Mis-folded proteins that have no corresponding enzyme matches for breakdown are shoved into the cell wall, and I believe wiggle on through the wall, exiting the cell during this shrinking and vibration. Alzheimer's may be the result of constipation in the brain, and A2-73 may be Ex-Lax for the brain as well as reducing the volume of this mis-folded protein waste to begin with.
I believe these findings are relatively new. Who knows what other strange things about the brain and about Alzheimer's will be learned in the future. But who cares why a given drug works if it works continuously and has no significant side effects. Patients like A2-73. That is meaningful all on it's own; again as long as whatever it is that they like lasts and has no significant side effects.
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I know this has been mentioned before but a hat tip anyway to Kyle76 for this in the comments section of a Seeking Alpha article.
"A little-discussed but, in my opinion, a key attribute that has been observed in A-273 testing is relief from insomnia, a very common and vexing symptom of many AD patients. Imagine the burden of a family member trying to care for someone who is up much of the night. Dealing with the many other symptoms of AD on little sleep has to be extremely difficult and probably leads to the institutionalization of many patients who might otherwise be treated at home. The promise of relief from this symptom alone is, to me, a huge factor in a medication that so far has shown few, if any, negative side effects."
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Regarding drug pricing: I watched the video Flipper.
I would feel worse about the high cost of drugs, being a biotech investor, if it weren't for my casual research on which Big Pharma might be a buyer for X startup. Looking at the big dogs... they are all in debt. Maybe not literally all of them, but most of them have huge debts. Kind of scary, and a pretty solid counter to the notion that they are overcharging for their drugs.
The issue of different prices for different countries... that is a different issue. Overall, most big pharma companies are apparently not charging enough to cover costs. Disturbing notion as high as drug prices are.
In general, being a technical professional, I have always seen the marketing overhead as somewhat of a waste. Maybe something could be done there. Maybe not.
I have long felt that the federal government should be a competitor in R&D for drugs. That aspect of socialism I agree with.
How long has the latest and greatest variant of "rPFS" been around?
If you are saying that deciding after initial trial design to add analyzing the data with a modernized rPFS type method would be as improper as adding a subgroup after the fact, then I would disagree, in spite of my respect for your opinion.
It's just not the same thing. The only reason to push that argument would be if you were a competitor saying, "They didn't say mother may I".
Immunotherapy is new. I believe that it is unreasonable to require all aspects of data analysis in a lengthy immunotherapy trial to have been defined up front when the knowledge of what is proper data analysis has mushroomed in recent years. That is the kind of flexibility that should have been added to the FDA decision making as the result of recent changes.
This particular issue of progression vs pseudoprogression is particularly important regarding the use of the most accurate method recognized by the FDA, regardless of when it was recognized relative to the trial design window. It does add another chance for a random good result, but to the extent that it is a better method, that random factor is limited. Combined with the FDA influence in a trial design that confuses OS... they should yield here if this is an issue in contention, and I believe they will; Though it concerns me a great deal that Reefrad seems to also think that late pseudoprogression confused with progression would jeopardize PFS. Still, in spite of you two heavy weights aligning on this, and in spite of the fact that I can't quite wrap my head around how to fix such a situation, I still believe that a recognized improved method for post analysis of progression vs pseudoprogression is a good thing and could some how be utilized to generate a more accurate picture of efficacy. And again, I believe that the FDA would consider such analysis in their consideration of approval.
I told you AVII would not approve it Sentiment.
However... if the data were still un-blinded when they came up with a convincing major improvement in assessing progression, then I would like to think there would be a small chance that the FDA would consider the post analysis as supplemental data regarding MPFS against AVII's objections, and in spite of the irreversibility of the actual crossover. Note that such a post analysis is not guaranteed to favor DCVax-L because it is conceivable that a control patient would have pseudo-progression and have it confused as progression. Maybe never happens, but no law saying it can't happen.
I think in the brain cholesterol is more of a structural material rather than a metabolic component. I think it is sort of insulation for the nerves / neurons/ axons? Not sure if it just makes for a good seal for ions or if the fact that it is a good electrical insulator comes into play.
Very different than other uses in the body. As someone pointed out, in addition to the metabolic functions described in the posted discussion about it's role in cancer it is at the very bottom of the chain of hormones and hormone like molecules. It is used to make both sex hormones as well as corticosteroids (not sure that is exactly the right term) which are needed in balance with the sex hormones or ... it gets harder and harder to breath and you feel like you are having a heart attack... and probably many other effects.
He did. After the great sp collapse for NWBO Woodford said that some of the collapse was warranted, but that it had gone way too far. He said that fair value for $NWBO is about $7 or so. He said it in exactly the same context as you quote him talking about Capita or whatever that other company is. $7 before positive P3 results! (and a little dilution).
I guess I asked for that. I won't do that again. Was Flipper's speculation about drawing a line at some high max median about OS or PFS? Could it apply to OS (if it was about PFS)?
"PATIENTS ARE LIVING LONGER" So your sayin it's all about OS? You sound like Doc Logic, LL, and Les (Goldman not Nessman), ... Any of you want to give an estimate for when we reach the OS endpoint?
"The only question left for me is whether or not all improvements to L have been included in this trial."
I was thinking exactly that just 2 minutes before reading your post. There is so much generally to be learned when the data is unblinded...
Maybe even information useful for Direct, but certainly for the DCVax-L / CI combo trial.
Even if they don't learn anything useful for the next trial, it wouldn't make much sense to not take a good look before pulling the trigger on any new trial protocols. Yet they claim to have already worked out a trial design for the L + CI trial... . But that might not be in stone quite yet.
One would hope that they use the latest technology to scrutinize the accumulated data as long as it is the first look at the data. If it is not the first look... then it gets complicated. AVII would not let them do that.
Yet another reason not to eat peoples brains.
Fantastic stuff Flipper! Regardless of the relevance to the DCVax-L trial, this information and the spirit of the presentations is tremendously encouraging for the future of immunotherapies and other cancer treatments.
Possibly automated cancer subgroup detection via automated image analysis. Possibly going on right now in post data analysis in the DCVax-L trial... including distinguishing real from pseudo-progression... I assume that is what you are suggesting.
Another related benefit for DCVax-L could be the following: I have been concerned about efficacy in the Mesenchymal subgroup because I have not heard anybody say that the subgroup can be identified in time to select DCVax-L prior to surgery. That would seem to be a logistical problem to me. If so, NWBO might need to get approval for the entire GBM population, which is more difficult. But this presentation suggests that there may be a non-invasive way to identify such subgroups before surgery using "Radiomics"; if not now, then possibly in the near future. This might influence the FDA to allow approval for that subgroup even though the logistics might initially be more burdensome than the FDA would like.
When I consider the silence by LP I weigh in both the trial sensitivity and the multiple legal case sensitivity. At least one of the legal cases has reached a head, while the Phase 3 trial is also at a critical point. That is a quite a combination of motivations for them to just shut up until solid data can be safely and confidently PR'd.
That is a fascinating paper!
Stillwell: This first page claims improved efficacy in combination, but doesn't say anything about reducing CI dose level. Do you have the full article? Does it say that they found that DCVax-L administration allowed them to reduce CI dose level and that this lead to, or should lead to less adverse events?
I am hopeful such is true, but does this report actually claim this?
"Mesencyhmals are doing better because they have more mutations and more targets compared to the other groups."
What doesn't make sense about that is that there are presumably scores if not hundreds of neo-antigens in every tumor type and DCVax-L presumably targets all of them. This is the model we have. Unless they have a new model... I suspect the difference has more to do with blockade function.
Good question. I have been wondering the same thing. Some posts on the topic are a little confusing. Many say that mesenchymal is more immunogenic than the other subgroups. Not clear if they are talking about more antigen targets or less blockade/checkpoint function, but some go on to say it has more expressed antigens.
I was somehow under the impression that mesenchymal is more vulnurable to DCVax-L due to having less blockade function, less brakes. I will have to research a little to see if I can support that. If so, then the CI's would make sense as a possible solution for the other GBM subgroups.
(If mesenchymal has less blockade function then why is it the most successful GBM subgroup? I assume that it has some other features that make it successful, outweighing the disadvantage of having less blockade function.)
"The Company has undertaken extensive analyses of data from the Phase I portion of the Phase I/II trial of DCVax-Direct for all types of inoperable solid tumors. The Phase I portion of the study involved 3 different dose levels, 2 different product formulations, 13 different cancers, several modes of image guidance for treatment administration and multiple measures related to immune system activation. Analyses of this data have found some novel, unexpected and encouraging results that are of significance for further trials. "
You should clarify that those comments are regarding the Direct Trial. If that was said of the DCVax-L trial, I would have a mixed feeling about it. But being from the Direct trial it is wonderful to hear.
"In the combination arm, they also still have time to lower the checkpoint inhibitor dosing even more..."
Sounds good. But I wish they would talk about that aspect of the trial. Well... not they. They have chronic laryngitis from the holiday pies and candy. But someone. I wish someone would talk about DCVax-L potentially reducing the hazard of the CI's when used in combo.
Not that you are not someone Flipper.
Some here have stated that they are hopeful that CI adverse events will be lower when used in conjunction with DCVax-L because the CI dose required will be lower. I am one of those hopeful people.
But has anyone every seen a study suggesting this or a researcher speculating such? Even if not, I will still be hopeful.
But CI's and brain cancer is a delicate mix. The adverse events for CI are run-away inflammation... I believe. And such in the confines of a skull is not only dangerous but very scary if it can happen faster than it can be treated. So that is the seriousness of the issue. And for a child to have to experience such is very sad. But then so is GBM in general. So...
Hopefully DCVax-L as a combo to CI's will net reduce this hazard.
Further, the planned combo trial is with a different CI than this AE.
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Adverse event child GBM --> Pembrolizumab --> Keytudra --> Merck
DCVax-L + CI for GBM --> Nivolumab --> Opdivo --> Bristol Meyers Squibb
Years ago when were debating these issues I found an article stating that many or most patients on TMZ eventually die from TMZ poisoning. I was super angry about it and sure TMZ administration was a mistake.
However, I kept thinking about it and realized that quality of life aside, the optimum administration would be 50:50 chance of the TMZ vs the cancer killing you. Something like that anyway.
However, the optimum level of TMZ when in conjunction with an immunotherapy would clearly be less than without the immunotherapy given that the way it kills you is that it destroys your immune system. So having a provision for SOC to be followed along with any new therapy being tested is counter intuitive if the therapy is an immunotherapy.
An example I sent to whoever might listen is the following: Say SOC was heating the tumor by 20 deg F with a small heater continuously for 6 months. But researchers want to test cooling the tumor by 20 deg F instead because it worked so well in rats. So the required protocol for the trial for the new treatment would be:
Control Arm: Heat the tumor by 20 deg F for 6 months.
Experimental Arm: Do nothing at all for 6 months.
So I hope RK is right that there is a limited dosing using TMZ. Not saying she is, but I hope she is.
"Wait a second, AF told us that's not possible so I sold my shares. Now what?"
Quit your griping! Tell to the judge buddy!
"suggesting that tumors did not change class at recurrence"
I hope that is the case. If not, then targeted treatment by subgroup gets sooo complicated. I am sure that people posting otherwise have some article to point to, but I hope that article is wrong. Cancer is tough enough without it changing fundamental type constantly.
DCVax-L + CI combo trial to target those non-mesenchymals makes a lot of sense to me. It might also serve to make the FDA feel better about approving DCVax-L for the whole ball of wax, because there is a plan in place that would build on it and fill in the gaps.
Kind of like ARGS bragging up their new lease for a mfg facility. It might take them years to get it up and running, but it also might make the FDA feel better about approving their product right now. Though I doubt it. But I think that is ARG's hope.
So also a convenient time for NWBO to show a follow-up plan regarding the whole ball of wax. Large scale Mfg is presumably already being addressed.
Of course. But it would be great reason for hope, if they need hope. Even if only to seal the larger deal. Myself I am a big fan of subgroup by subgroup unless... DCVax-L is the solid base from which to expand for all subgroups even the current low efficacy subgroups, assuming they exist. Which it might be. And then Prins work posted today and the planned phase 2 with DCVax-Lung ;) and the CI might fill in the gaps.
Yes. I agree. Could be. (I see now you weren't really asking me).
Sentiment: An improved post-analysis of late progression as pseudo or otherwise might repair the data in terms of PFS. However, because patients (are rumored) to not always go to (or continue) DCVax-L after progression, you could end up with some patients initially on DCVax-L that showed late progression and so gave up on DCVax-L when in fact the late progression was pseudo-progression, thus a sign that DCVax-L was working.
All this assumes that part of pseudo-progression determination is a believed limited window in which it can occur. This presumes that model was wrong. Maybe it was correct before DCVax-L, but is no longer correct.
I know this is rehash for you Sentiment. And Flipper and RK etc... . But I don't remember what you guys dug up about this window issue.