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Congrats to Adam Feuerstein and his market moving news released just over an hour ago. This early data suggests that this Gilead drug could be a game changer.
STAT News have reported on some early data from the Gilead remdesivir studies in COVID-19 patients.
Prof Stephen Evans, Professor of Pharmacoepidemiology, London School of Hygiene & Tropical Medicine, said:
“There are three Gilead sponsored studies on clinicaltrials.gov. One is the “trial” which has the leaked data in severe patients; a second “trial” is the same but in moderately ill patients and the third is their expanded access program, initial results of which were published in the NEJM. In each of these studies any comparisons of the benefits and harms of remdesivir rely upon external, non-randomised comparisons. These are always difficult to interpret, which is why in virtually all instances, medicines regulators require randomised comparison with current standard of care (including a placebo group in most instances for drugs). There are no “proper” RCTs listed with Gilead sponsorship which show an intention to demonstrate efficacy compared with a concurrent randomised group. It makes it very difficult to interpret, which is what is said in the article “The lack of a control arm in the study could make interpreting the results more challenging.”
“None of these studies is what should be done for a new treatment with unproven efficacy. They all depend upon non-randomised data for estimating efficacy. There is a danger that this strategy, of not using a randomised comparison group, could exert pressure on patients, health professionals and possibly even regulators to grant a licence for the product. It is going to be very difficult to begin a genuine RCT comparing current standard of care with remdesivir in the future, but there are several ongoing trials, not sponsored by Gilead, which are running currently. Provided Gilead has not restricted access to their drug for these trials and they have managed to recruit and follow up sufficient patients, we have the hope of finding whether remdesivir does have genuine efficacy and safety based on good evidence. Medicine is littered with instances where treatments were believed to have strong benefits based on non-randomised data (an example is the effect of combined hormone therapy on cardiovascular disease).”
Scotty. How do you do it?
Works every time.
The big bad wolf?
Pharma reporter on the line to Dr Buzdar:-
'Dr Buzdar, can you tell us what you think about the leaked preliminary findings from the Remdesvir trial?'
Dr Buzdar- 'Well, I consider it highly irregular. In all my time, I have never come across such a blatant disregard of the requirement not to push preliminary findings from a trial of an unapproved drug.'
Reporter- 'Hey, Buzzy, it's me Adam'
Dr Buzdar- 'Well why didn't you say? Hrmmph. As I was saying, at this time of huge international anxiety, when everyone is looking for a glimmer of hope, I think it is perfectly acceptable for good news coming from trials to be publicised as early as possible'
Reporter- 'Thanks'.
Hey abeta.
I tell you what is difficult to ascertain; if you are IDH mutated (good) and MGMT methylated (good), do you get a double dose of good prognosis?
In other words, how much overlap is there between IDH status and meth status?
Never actually been able to find that out, because most papers tend to have a focus on one or the other.
Damn, I only went and picked a Sunday...
(I shall have to have a word in LP's ear)
At the end of the day, when the chips are down, and the fat lady sings, there is really only one thing to do.
Hi meirluc.
Bit late in the day for me, and I'm struggling to get my head around the calculations!
I'll try and respond tomorrow.
Nearest wins right?
NWBO poll - Top Line Data
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8/2/20 Longfellow
She didn't say that collecting the IDH data (however they do it) would cause any delay.
I'm assuming that they have already allowed for it in their timeline.
Just a bit of sensible clear advice that UK citizens are currently receiving, which others may find of benefit:-
Latest press release on Covid-19 ??
As we enter the next 3 weeks of lockdown here is a summary of the advice:
1. You MUST NOT leave the house for any reason, but if you have a reason, you can leave the house
2. Masks are useless at protecting you against the virus, but you may have to wear one because it can save lives, but they may not work, but they may be mandatory, but maybe not
3. Shops are closed, except those shops that are open
4. You must not go to work but you can get another job and go to work
5. You should not go to the Drs or to the hospital unless you have to go there, unless you are too poorly to go there
6. This virus can kill people, but don’t be scared of it. It can only kill those people who are vulnerable or those people who are not vulnerable people. It’s possible to contain and control it, sometimes, except that sometimes it actually leads to a global disaster
7. Gloves won't help, but they can still help so wear them sometimes or not
8. STAY HOME, but it's important to go out
9. There is no shortage of groceries in the supermarkets, but there are many things missing. Sometimes you won’t need loo rolls but you should buy some just in case you need some
10. The virus has no effect on children except those children it effects
11. Animals are not affected, but there is still a cat that tested positive in Belgium in February when no one had been tested, plus a few tigers here and there…
12. Stay 2 metres away from tigers (see point 11)
13. You will have many symptoms if your get the virus, but you can also get symptoms without getting the virus, get the virus without having any symptoms or be contagious without having symptoms, or be non contagious with symptoms...
14. To help protect yourself you should eat well and exercise, but eat whatever you have on hand as it's better not to go out shopping
15. It's important to get fresh air but don't go to parks but go for a walk. But don’t sit down, except if you are old, but not for too long or if you are pregnant or if you’re not old or pregnant but need to sit down. If you do sit down don’t eat your picnic
16. Don’t visit old people but you have to take care of the old people and bring them food and medication
17. If you are sick, you can go out when you are better but anyone else in your household can’t go out when you are better unless they need to go out
18. You can get restaurant food delivered to the house. These deliveries are safe. But groceries you bring back to your house have to be decontaminated outside for 3 hours including Pizza...
19. You can't see your older mother or grandmother, but they can take a taxi and meet an older taxi driver
20. You are safe if you maintain the safe social distance when out but you can’t go out with friends or strangers at the safe social distance
21. The virus remains active on different surfaces for two hours ... or four hours... six hours... I mean days, not hours... But it needs a damp environment. Or a cold environment that is warm and dry... in the air, as long as the air is not plastic
22. Schools are closed so you need to home educate your children, unless you can send them to school because you’re not at home. If you are at home you can home educate your children using various portals and virtual class rooms, unless you have poor internet, or more than one child and only one computer, or you are working from home. Baking cakes can be considered maths, science or art. If you are home educating you can include household chores to be education. If you are home educating you can start drinking at 10am
23. If you are not home educating children you can also start drinking at 10am
24. The number of corona related deaths will be announced daily but we don't know how many people are infected as they are only testing those who are almost dead to find out if that's what they will die of… the people who die of corona who aren’t counted won’t be counted
25. You should stay in locked down until the virus stops infecting people but it will only stop infecting people if we all get infected so it’s important we get infected and some don’t get infected
26. You can join your neighbours for a street party and turn your music up for an outside disco and your neighbours won’t call the police. People in another street are allowed to call the police about your music.
27. No business will go under due to Coronavirus except those businesses that will have already gone under.
This one has been revisited lots of times.
My view is that it is not a 'clean' control arm, due mainly to crossover. Others won't see it that way.
Purely from a data point of view, you ideally want it as clean as possible; both arms being identical in every respect, except that one gets the experimental treatment and the other doesn't.
But we haven't got that. But I think most agree that if treatment OS is exceptionally good at 3, 4, and 5 yrs, it won't matter, or at least it shouldn't matter. At these timepoints, the treatment arm will outperform the equivalent data from Optune point for point, with perfect safety, and a maintained quality of life.
ilovetech.
I'm not surprised to see a company using a variation on the theme.
The theme being an autologous dendritic cell therapy. There have been others that came to nothing.
But seeing as I do believe in DC therapy being the most genuinely promising strand of immunotherapy, I would not dismiss out of hand a similar approach being adopted by another company.
But this one is about where NWBO were at a decade ago.
It's a single arm P2 of 55 patients, though they are monitoring a matched control cohort. I wonder if the matched control patients know they're being monitored in that way and whether they consented to it..
Their figures are confusing. At the top they state 1yr survival (OS12) of 76%, which is nothing to write home about at all.
In our trial the blended OS12 is 89.3%. They then say that survival at 15 months is also 76%, which basically means that none of their patients died between 12 months and 15 months, which is unlikely, but possible.
But then later in the release they say, that back in 2019, they had OS12 of 91%. In other words, their figures have deteriorated over time.
And unless you know what split of the 55 is meth, you really can't draw any conclusions at all.
Honestly, OS12 of 76% is not much better than what you would expect of SOC these days.
And with any DC therapy (or ICI come to that) you're always looking for the long tail. So you need OS24 and beyond, before you can draw any real conclusions, and they simply are not there yet.
So very similar to L, but they are probably using plain old tomayto sauce, because they don't have any secret sauce.
I would file it as not an imminent competitive threat, and probably not ever a serious threat.
It's really the GBM P3's that are within a year of readout, that need to be watched, and there is none that I am aware of.
Though there will be some about, but if they involve an ICI, I dismiss them as 'will fail'
Not saying that is necessarily wise though.
Here's their CT listing if you want to check them out further, to compare inclusion / exclusion criteria etc.
https://clinicaltrials.gov/ct2/show/NCT03400917?term=NCT03400917&draw=2&rank=1
Ta for that, Lykiri.
Interesting bunch of participants.
The woman from Imperial College. Imperial College is given tons of money not only by the UK Govt, but also by Bill and Linda Gates, no less. It's all to do with his vaccine agenda (not just Corona) ('Vaccinate the entire world for absolutely everything')
And Imperial College came up with the (crazily inaccurate) report to the UK Govt, predicting that about half a million citizens would likely need hospitalising, that led to the UK lockdown decision.
Chap from Oxford Biomedica. Oxford Biomedica is part of the UK consortium working on a Corona vaccine, and so is Cobra Biologics (Cognate)!
Prof. Farzin Farzaneh from King's was involved with the UK bit of the L trial a few years back, when it was proposed that King's would do the UK DCVax-L manufacturing, though that never happened for some unknown reason. And he surely knows Dr Ashkan.
Advent Bioservices. No, never heard of them.
I honestly do think that there is a chance that some of Sawston might end up being used for Corona vaccine manufacture, if this consortium wins out from the dozens of other groups trying to do the same thing around the world. But, if that came to pass, NWBO would surely derive considerable income for the use of their facility, and Advent would have more work than they could handle in a lifetime.
Oh, and the other thing I just thought of, is that a regulator SAP response might have been; 'You are testing all for IDH status aren't you?'
And LP thinks to herself; 'Oh bugger, that's another $50k gone in testing fees'...
In a couple of weeks, I'll mark my two year anniversary discovering Investorhub and NWBO.
No, the prevalence of IDH mutation in an undifferentiated GBM population is generally quoted at around 5% (and just to complicate things further; of those 5%, 90% are IDH1 mutations and about 10% are IDH2 mutations!)
But you will of course find quoted 3% here or 7% there quoted depending on which particular paper you're looking at.
90% of an undifferentiated GBM population are primary GBM's (all or very nearly all wild-type), and about 10% are secondary GBM's. And half of those secondary GBM's (approx) are IDH mutated.
So you add the 90 and the 5 and you get 95% wildtype, 5% mutated.
Why is LP making an issue of it? Well, she may not realise the relative lack of significance (certainly compared to meth / unmeth) of IDH status, or she just wants to give a variety of 'more chances to win', which it isn't, tbh.
And maybe even to draw away attention from gene expression profile.
This Board has discussed for years the issue of how L might be extra beneficial for mesenchymal, following the LL hint in that direction. (Yes, all based on them 23 patients.) And while that discussion is interesting; in this trial, subgrouping by gene expression profile simply isn't going to feature at all. I don't think any of the patients have been tested for gene expression profile, certainly not all of them.
And we now know that it's a movable feast anyway, with gene expression that can differ over time (usually shifting to mes by time of recurrence), and also might vary between two samples taken from different bits of the same tumor (intratumoral heterogeneity).
They knew they were giving a slimburger, so just wanted to give a tiny sidesalad. And as we know, tiny sidesalads don't have much nutritional content; they're just there to make the plate look a bit more colorful.
(Somebody is bound to tell me that there is a lot of nutritional benefit in a side salad...)
But, we did get a firmish timeline.
And that is surely significant (and maybe a relief for some).
So we now know that time to topline is finite. For better or worse, it's going to end.
And given the fairly tight time estimation for that event, if there is a bit of further unavoidable Covid slide, then they should just openly update us as we go.
Hopefully, there will now be a reduction in the 'they will never end this trial' and the 'it's failed already, they just won't tell us' type of stuff.
And if there is, I will be rather grateful.
God knows what the short term market reaction might be.
Imo, it should be basically market neutral, (no-one is going to sell off the back of it, but I doubt if much new money will be enticed in either), but short term share price movements seem to be largely dictated by bits of manipulation here and there, and not a lot else. Of course, I have no real idea, and some might have heard enough to jump back in a bit more.
Well, it's a known significant positive prognostic indicator.
But seeing as it was only identified / discovered in 2007, I wouldn't go so far as to say its a known confounder in clinical trials, particularly as it constitutes only 5% of a typical GBM population.
Nothing like meth status, where you have an approximate 60:40 unmeth / meth split, with meth having a huge prognostic advantage compared to unmeth (though some reckon the advantage is related to being predictive of getting benefit from TMZ). But either way, prognostic or predictive, meth confers very considerable survival advantage.
You absolutely must stratify for that, so that you have similar proportions in both your investigational arm and your control arm, in the same way you would (or should) for age, extent of registration, gender, and probably one or two others I've forgotten. Unless your trial is only for meth or only for unmeth of course.
But if you actually collect IDH mutation status for all patients, even if you didn't actively stratify for it at the outset, I guess it would be good practice to report in your paper that, along with age, eor, gender, and meth status being spread proportionately, so was the small percentage of subjects with IDH mutations. If indeed that was the case.
Which has got me wondering if it was reported in EF-14, and I'm not altogether sure. I don't think the FDA even mentioned it in their report about the trial that led to the approval.
So I would say yes it should be accounted for, so that proper control and propriety is demonstrated.
And it would be interesting to know how the handful of IDH mutated patients did on DCVax-L, but the numbers would be so small that (imo), you could only use that info as a bit of exploratory analysis.
The World Health Organisation has actually given diffuse gliomas with IDH mutation a separate classification, so it could in some respects be viewed as a somewhat different glioma altogether, compared to the other 95% of GBM's.
https://www.pennmedicine.org/cancer/-/media/event%20media/2018/cancer/06%20june/brain%20tumors%202018/the_new_who_prokop.ashx?la=en
IDH Status.
All GBM's are either IDH mutated or IDH wildtype.
Subgrouping based on IDH status isn't viable in statistical terms.
Because:-
90% of GBM's are primary / de novo GBM's.
And 95% of primary GBM's are IDH wild-type, some report it at 99 or 100%.
Secondary GBM's (preceded by a lower grade glioma) make up about 10% of all GBM's.
And something like 40 or 50% of secondary GBM's are IDH mutated.
Thus in any broad GBM population, only about 5% will be IDH mutated.
Translate that to our trial and that gives you about 16 of the 331 being IDH mutated.
Perhaps 5 in the control arm, and 11 in the treatment arm.
Straight away, you can see that the numbers are so small, that arm by arm comparison based on IDH mutation is a statistical non-starter.
There is a distinct group of GBM patients that have a few common characteristics. These are secondary GBM, much younger age, Proneural gene expression, and often IDH mutation. And if you fit into that group, you have a considerably better prognosis, perhaps 50% longer OS expectation.
(Kat Deeley was likely one of these.)
The prognostic importance of this grouping rivals the prognostic importance of methylation status.
But as stated, the numbers in our trial with IDH mutation will be small; in the region of 5%.
So why does it matter at all, and why did LP flag it up?
Well, I actually don't know why LP flagged it up, seeing as it was somewhat downplayed in JTM.
But the reason it could be of a bit of importance, is that it is a worthwhile exercise to check that IDH mutated patients are in the same proportion in the control arm as the treatment arm.
It's almost implausible, but what if a large proportion of the IDH mutated patients by a quirk of fate ended up in the control arm?
It would skew your results somewhat.
So if you can check it, it's worthwhile to do so.
In practice, because of the age stratification that ensures median age is basically the same across the two arms, it's very unlikely that one arm would have significantly more of the handful of IDH mutated than they should.
Now you could say that because the trial population of 331 is a few years younger than 331 patients in the general GBM population, that our trial might just have 2 or 3 more patients with this prognostic advantage than you would normally expect.
But that really would be a very small factor.
Of course (as I've said previously), if you were running a single arm trial with just historical control, you could pull a fast one and stack your trial with loads of secondary GBM patients who will also likely be IDH mutated. But not really advisable to do that, because it's (a) unethical and (b) you might get rumbled...
I only know the above because I've read and distilled dozens of papers on the subject over the last couple of years.
Any one individual paper might give slightly different percentages to mine, but I've tried to give average figures based on quite a few papers.
Good man, HB.
Thanks.
Is it on medium wave or long wave by the way?
Only just realised happy hour is over.
After wasting a load of posts talking about golf, this is my 15th post!
Over and out for today.
OK Flip.
Shall we reconvene this in six months?
Flip.
The golf analogies are just a bit of idle banter.
(Though the unanswered questions about a vaccine are real enough for me..)
But anyway, here's some more, confirming that what people should do and what they actually do is not always the same!
The vaccine is a short putt.
Hmmm.
The jury will be out for a long time on that one.
https://www.nytimes.com/interactive/2020/04/16/opinion/coronavirus-mutations-vaccine-covid.html
HB. Just wondering if you've worked out equivalent UK start time?
Yes, there's a development race for sure.
But safe and efficaceous?
The money-making potential is huge that's for sure.
Which it wasn't in the case of coronavirus treatment.
(Though Gilead will hope to make hay while the sun shines with remdesvir.)
Mass vaccinations are not without risk.
Plus we have a fast mutating pathogen, which will likely require annual vaccine re-formulations, similar to the flu jab.
Not to mention the issue of the vaccine being placed somewhere in that nebulous region between universal and mandatory..
Yes, Marzan, that's why I just said 'listed'. I didn't say they were all active. Some haven't started, some are recruiting, some are active, not recruiting, some are in no man's land. I really haven't looked at them all. I'll have to look to see if any have results posted. I know there won't be any with good results.
On the apparent pembro monotherapy, which hasn't started, I agree.
ICI's as monotherapies have already demonstrated failure in GBM, and I doubt that will ever change. As well as being non-effective in GBM, the ICI's bring a lot of toxicity the table.
Cases of ICI hyperprogression in GBM have already been documented.
And I doubt that any Keytruda combo that involves TTF or Bevacizumab will do any good either (notwithstanding the fact that Optune somehow got approved).
The novelty in this trial is the upfront administering of the pembro, but I have my doubts about that making much difference, despite the early Prins findings. Though I do hope we get some initial findings well before the projected 4yrs.
With fries.
Damn ratpack are at it again.
It's just an ASM, Ex.
Probably best if you don't expect too much.
I expect the term 'compassionate use programs' to widely substitute for UK Specials, though it's understandable why they might need to do that.
So what does Saturday bring?
It's a bit of an oddball P2 in my opinion.
It certainly not registrational.
And it re-introduces the use of the poly ICLC adjuvant (both arms).
Which is just adding another ingredient, which will complicate the results interpretation somewhat.
But yes the DC vaccine (whether we call it L or not) is the comparator arm.
But we have to bear in mind that Keytruda is listed in about 27 GBM trials, with every combo under the sun, including a combo with TTF (wouldn't want to be on that one..), so while the trial is definitely interesting, and potentially information rich, results are 4yrs away,
I don't read much into it, as to what it might suggest about a wider NWBO / Merck relationship.
Merck can afford to employ a scatter gun, mud against wall approach, to see what sticks.
My hunch is that L plus poly ICLC will do better without the pembrolizumab.
Anyway here's the trial
https://clinicaltrials.gov/ct2/show/NCT04201873?term=pembrolizumab&cond=glioblastoma&draw=3&rank=11
And here's the other 26!
https://clinicaltrials.gov/ct2/results?cond=glioblastoma&term=pembrolizumab&cntry=&state=&city=&dist=
Yes it will.
Yes, it did.
Mission accomplished.
Why you feel the need to praise him, I have no idea, but it is one of the odd things on this bulletin board.
Ah.
If you had said after-market action, I would have clocked it.
Well, it was worth the 'powers that be' letting AF out to exercise Bo then.
Everything else I stated still holds though!
Disgraceful (and I mean that) pumping of an unapproved drug that's been in one of the shortest P3's in history.
Note how they got non-company spokespersons to do the pump.
Hi meirluc.
I've just come into line a bit with your calculation.
But I reckon 40-50, with 50 tops.
Regards.
Leprecon.
On the basis of your post and your model (and being reasonably confident that aggregate OS60 will reach 20%), I'm going to up my CI a smidge to 40-50 alive.
Can't remember exactly what was meirluc's range, but I think I'm more or less in accordance with him now.
Congrats to Adam Feuerstein and his market moving news released just over an hour ago. This early data suggests that this Gilead drug could be a game changer.
Jerry.
It's plain to me that if you put up a comparison using two comparitive percentage figures, you should be clear about whether you are using different date ranges or not.
Why use the NWBO start date at its share price zenith, but not say that you are doing that.
No humour and no daftness from my perspective.
If you want to consider it daft, then that is of course your prerogative!
Who is defending it?
I'm not.
For anyone who went in very big in 2015 and has a high average price, it's nothing short of a disastrous investment.
But who is responsible for that?
That's a different question.
And I don't lay all the blame at the door of the company management.
I certainly wouldn't invest in another OTC bio microcap, because of their vulnerability to shorting and general share price manipulation.
Something I wasn't aware of, when I first invested in NWBO.
I don't know why some are quick to place all the 'blame' at a single door.