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Yes, a subset. But if it works (IMO unlikely) BMY could easily beat NWBO to submitting a sBLA.
Scotty. It works every time.
Good to see it picked up by the NY Times.
https://www.nytimes.com/reuters/2020/05/31/world/europe/31reuters-health-coronavirus-italy-virus.html
Thanks, HB. What an important report, though you can guarantee it will not see the light of day in certain sections of the media.
And it basically lends confirmation to my view that the virus is quite rapidly losing virulence, and those now testing positive are generally experiencing a very low viral load.
A quick perusal of Italy and Spains (two of the hardest hit countries) steadily decreasing fatalities demonstrates this.
As this evidence continues to come in, one hopes that there will now be a widespread steady lifting of no longer evidentially justified social restrictions across the world, allowing for all current international drug clinical trials to resume normal processes.
In many international trials, conducting of routine trial procedures has been difficult or near impossible.
One hopes that the DCVax trial processes had already virtually completed before restrictions were adopted, and that any outstanding loose ends can be rapidly tied up.
“In reality, the virus clinically no longer exists in Italy,” said Alberto Zangrillo, the head of the San Raffaele Hospital in Milan in the northern region of Lombardy, which has borne the brunt of Italy’s coronavirus contagion.
“The swabs that were performed over the last 10 days showed a viral load in quantitative terms that was absolutely infinitesimal compared to the ones carried out a month or two months ago,” he told RAI television.
Italy has the third highest death toll in the world from COVID-19, with 33,415 people dying since the outbreak came to light on Feb. 21. It has the sixth highest global tally of cases at 233,019.
However new infections and fatalities have fallen steadily in May and the country is unwinding some of the most rigid lockdown restrictions introduced anywhere on the continent.
Zangrillo said some experts were too alarmist about the prospect of a second wave of infections and politicians needed to take into account the new reality.
“We’ve got to get back to being a normal country,” he said. “Someone has to take responsibility for terrorizing the country.”
Have to admit that they are my estimation of likelihoods, rather than a bookies.
There is supposed to be a Jun 30th deadline on extending the transition period beyond the end of the year. But I think that is pretty meaningless. It's one of those moveable deadlines I think.
All the focus is on trade talks, which are going on behind the scenes, but without any sign of agreement.
Medicine regulation is just one of those forgotten afterthoughts, though NWBO will be an interested bystander monitoring developments. Though maybe a bit more than a bystander if they have been co-opted into something else to do with manufacture.
But although there is very little information out there on post-Brexit UK drug regulation, it is interesting from the Covid vaccine approval standpoint.
UK is hellbent on jabbing everybody at earliest opportunity.
Speaking of vaccines:-
Do they have ability at all to manufacture in the EU? Advent is the contract manufacturer for them over there, but all Advent has is in the UK which might be useless post Brexit.
Wow, thanks meirluc.
I will take a detailed look and get mine up in the next few days.
Actually, for ease of quick interpretation, do you fancy converting numbers to percentages? (e.g. OS24=50%)
General corporate purposes, of course.
Mind you, that promo show wasn't worth what they paid for it.
The large payment to the CRO is just some speculation that there was no need to guess because it is likely not even true. They have been paying the CRO for over a year to scrub the database and it was mostly done a year ago. Whatever is left is not that much.
Hi meirluc.
I genuinely hope you are right, but on this issue I think it may pay to be a realist rather than an idealist.
Time will tell.
How are your figures going?
The timeline for mine has been put back a week!
(But I never actually promised them by now..Lol!)
NOW THE COLD TRUTH IS THAT THE COMPANY WILL DATA LOCK IN MAY,
Yes indeed, if they knew a while back that they were going to run significantly into June before datalock, they could have told us already.
But that might mean datalock is really imminent.
We'll see.
On this particular issue of datalock.
What they said at ASM:-
“We are excited by the progress that we’ve been making in finalizing the data and moving toward data lock, unblinding, and topline data. I will mention as a bit of context, when we set the date for this annual meeting back in mid-February---it seems like a lifetime ago---at the time we were in the late stages of the final data collection and confirmation. And as we all know all too well the world was very different. Hard to believe that was just two months ago. But the pandemic situation had not taken hold, even Italy only had a few cases, nobody was under any lockdowns and our contract research organization the CRO and our various service provider firms that we work with on this process of data collection and confirmation were working steadily with the hospitals that have been the clinical trial sites. Not long after setting the meeting date the whole world changed in a very big way as we all know. By early-March the hospitals had stopped by actually the beginning of March the hospitals stopped allowing the in-person monitoring visits that are necessary to check and confirm the data and they themselves became so overwhelmed that they really couldn’t help with the final data checking and confirmation, things like looking up pathology reports in the archives, when their emergency room and all of their wards at the hospital were flooded with patients.
“I’m happy to report that we have managed to continue moving the process forward, collecting the data. We developed some workarounds, like everybody. We’ve used Zoom, we’ve used email, we’ve used other information sources. We’ve gotten creative. And one of the reasons, we know that a lot of firms, companies who have scheduled their meetings for April have cancelled them and made plans to reschedule but we wanted to go ahead with our meeting because we’re proud of the progress and excited about the progress that we had already made and have managed to continue to make during what has pretty much been a shutdown for two months in March and April.
“And so, I wanted to just go through with you now where do we stand today and what do we believe will be the timelines to the remaining steps for announcing the data. Based on where we stand today, with the remaining queries, the remaining confirmations to be done with the hospitals, which we are assuming we will be able to do at least some work with during May, we anticipate that we will reach datalock by approximately the end of May.
Hi Senti.
Yes agree with most of your points.
L trial inclusion / exclusion criteria much the same as most ndGBM trials. Same median age, same percentage of meth patients, same extent of resection (except a few trials let in a few biopsy only patients). So it would be completely wrong to describe the population as 'dramatically different' to other trials.
The trial population is different to the broader GBM population out there, which tends to be a few years older, includes lower bloodcounts etc etc. But again all the trials do the same thing.
Not sure that all the patients in the trial are primary GBM.
But I suspect it'll be no more than 10% with secondary GBM, and as you say about half of those will be IDH mutated. So perhaps 5% of ITT are IDH mutated.
And seeing as they are apparently in the process of retrospectively testing all for IDH status, we will find out the figures, probably after topline when a fuller results paper is released or presented subsequently. I've no reason to think there is any sort of excess of mutated IDH patients, compared to other trials.
Yes, NWBO kept out those who had apparent progression (which may have been SOC pseudo-progression) during concurrent chemorad.
Again, what nearly everybody else does.
When you have PFS as an important endpoint, you simply don't randomize somebody who shows a suspicious spot (which could be either progression or pseudo-progression) on the last scan a week or two before intended randomization!
The difference with EF-14 is that, in that trial, if a patient had SOC progression / pseudo-progression, they waited (as long as necessary it seems), until they could determine if it was real progression or pseudo-progression before randomizing. If it turned out to be confirmed progression, then barred from trial, if pseudo-progression then admitted. Which gave EF-14 a significant advantage..
As to L-related pseudo-progression, yes we know it became an issue.
And we know that they intended doing the expert panel adjudication to review PFS calls.
We don't know what transpired about that, and we don't know what status PFS retained in the last revision of the SAP. I'm not suggesting it is being jettisoned, but the indicators, such as they are, suggest that the major focus will be on OS.
Personally, I doubt if the pseudo-progression issue led to the partial hold.
It may not matter what was the cause the hold. Until we know what it was. Only then will we know how much it matters in terms of trial outcome. And we might never know.
If any of that makes any sense.
Regards.
I don't pretend to understand options and warrants and such like.
I do expect they will have a sizeable final bill to pay to the CRO, at some point in the not too distant future.
Do you have a rationale? What is in play? Is it about the financing or non-appearance of Datalock PR?
I was playing daft, when I asked whether something was happening on Monday.
I'm not expecting anything to happen on Monday.
So why should we get hammered? A modest pullback wouldn't surprise, but why hammered?
By the way, I agree that it was just 1 or 2 buyers gradually accumulating over the last fortnight. I kind of hoped they had a bit more ammo to come. Maybe they have, maybe not. Perhaps a small hedge fund. And maybe an investment of around $5m (based on excess volume).
I don't think that the buying surge had anything to do with the L trial. But equally such investments are rarely made just on a whim..
So I'm still of the view that it was about something else.
And clever money buyers do not expect the share price to get hammered!
Financing was what it was. As I've said before, I'd rather see LP do a zero interest personal loan to the company. That would give all the right messages to shareholders. I expect she has the resources to do so.
But the fact remains they have to stay solvent. Nobody would thank them if they failed to do that.
And on datalock. They don't have to PR it. But why wouldn't they?
So I'm assuming it hasn't happened.
If there is a delay due to Covid restrictions on travel or access that compromises final query resolution and data scrub, they should just update us accordingly. Hardly difficult.
Because if they don't, as June progresses, shareholders who take timescales maybe a bit too literally, will start to get the niggles.
Is something happening on Monday?
Le gouvernement britannique a indiqué vendredi qu'aucune exemption n'avait été accordée aux Français pour la quarantaine qu'il entend imposer aux voyageurs arrivant de l'étranger dans le cadre de la pandémie de nouveau coronavirus, une annonce apparaissant comme un rétropédalage.
Thanks for the link.
So France is opening borders on 15th June to tourists from Germany and Italy, but not the UK?
Could it be something to do with the UK having the highest deaths in Europe?
Whadya think?
Hi Doc.
I'm afraid I don't consider it a 'voluntary' hold..
Whatever it was called, I'm of the view that it was at least a de facto mandatory hold.
It was only lifted when the FDA decided to lift it!
But yes, the 5-ALA theory doesn't obviously jibe with the probability that the last 30 or so patients all went to treatment.
(Though it remains possible that the randomisation skew could have been introduced at a different time, or for a different reason.)
I'm not asserting that this was the cause of the hold; just that for me, it is up there as one of the more likely possibilities.
As to it being a continuing hold, I think that fits quite well with some sort of required equivalency test or perhaps a related shelf-life test, which would necessarily take a long time to perform.
Even if ultimately it has no bearing on trial outcome, I would like to know what the hold was about..
I'm just so damn curious about it!
Well. Andrew Sloan clearly thinks it's more than just another advanced surgical aid:-
Andrew Sloan, MD, who holds the Peter D. Cristal Chair in Neurosurgical Oncology and serves as Director of both the Brain Tumor and Neuro-Oncology Center, and the Center of Excellence for Translational Neuro-Oncology at UH Seidman Cancer Center and UH Cleveland Medical Center; Professor of Neurosurgery, Case Western Reserve University School of Medicine, has conducted clinical trials with 5-ALA for almost a decade via his own FDA-approved Investigational New Drug clinical trial. The drug, which has been the standard of care in most of Europe for many years, causes cancer to fluoresce, which helps surgeons better identify the edges of the tumor and safely remove more of the mass than using traditional visualization methods.
“The goal is maximal safe extraction of the solid portion of the tumor,” Dr. Sloan explains. “With gliomas, you can never take every single cell out, but we know that 99 percent of the tumor is contained in the solid mass. So being able to clearly visualize those boundaries is a real advantage.”
Nearly 16,000 Americans are diagnosed with malignant gliomas each year. Most live fewer than 2 years after diagnosis, but more complete removal of the tumor can extend that.
“It’s very clear that patients do better and survive longer if you can take out as much of the tumor as possible, and any tool that helps you do that helps improve patient outcomes,” Dr. Sloan says.
In fact, patients whose tumors are removed with 5-ALA typically survive twice as long as others, he adds.
LIGHTING THE WAY
Dr. Sloan says his research protocol for using the drug is very similar to what was approved by the FDA last year. Thanks to that approval, he now uses 5-ALA in virtually every applicable case.
Resection using motor-mapping and 5-ALA
Patients don’t notice much of a difference other than taking the drug by mouth before surgery. Most healthy tissue can metabolize the drug to hemoglobin, a component of blood. However, cancer cells cannot fully process the drug, which accumulates as Protoporphyrin IX and causes malignant brain tumors to glow or fluorescence as pink under blue light. The surgeon uses a specially modified surgical microscope to turn blue light on and off during the procedure to guide the excision. This process only adds a few minutes to the overall surgical time.
“To a large extent, the invading edge of the tumor looks a lot like normal brain,” Dr. Sloan says. “It can be very hard to tell the difference, especially toward the end of the operation when the brain is starting to sag and shift, and the pre-op stereotactic imaging is no longer as precise as it was at the beginning of the case.
“By making the tumor turn pink under the blue light, it makes it easier for the surgeon to know when he or she has the tumor’s boundary. Once you hit that boundary and it’s no longer pink, then you know you need to stop or you risk damaging healthy brain.”
This approach, which Dr. Sloan predicted will eventually become standard of care nationwide, is approved for treatment of Grades 3 and 4 gliomas. He and his colleagues are exploring other indications for it, as well, he says.
He discussed that there have been numerous advancements in the field over the years. For example, look at UCLA where they discuss functional mapping and awake surgery. Not only are we seeing more complete resections, but also resections of boarderline areas that previously would not have been touched out of concern for damage.
His conclusion was that what is important is that the center have advanced technology and the doctor be expert at using it. Not that any one technology was the key.
I think Sushifish has swum off again.
Hi meirluc.
Still working on my figures.
But so far, I've concluded that nearly all of the 38 subjects with unknown meth status were in fact unmeth.
This can be reasonably deduced purely by what we already know.
At least the unknowns performed as if they were nearly all unmeth.
You would have expected 60% of them to be unmeth, but I reckon nearly all of them were.
At the moment, I have meth treatment 5yr survival looking to be in the region of 36-40%, with control about 20-22%.
(Which will completely blow Optune out of the water...)
But still some refining to do on the delta.
If those figures were born out, they wouldn't be a bad highlight statistic in a topline PR.
Obviously unmeth will be considerably less impressive.
Think this guy did previous with a negative slant.
So now he is hedging his bets a bit.
But he still perpetuates the fallacy that the trial was 'halted' for 2yrs:-
To further complicate the matter, in 2015, the Food and Drug Administration halted DCVax-L's clinical trial.
Even with a potential survival head start compared to other clinical trials due to a screening criterion requiring patients to be progression-free before enrollment, patients' survival in the two cohorts of DCVax-L's clinical trial compares very favorably to historical rates.
I always thought they were a stagecoach company.
Stock wont rally past .40 on the announcement of data lock.
JD. We've left the 0.20's behind..
I know it's a shock.
Here in the States, it is often used as a figure of speech to mean an intentional effort to slow things down.
Umibe. Thankyou for feeding back from your conversation.
'FWIW'.
That indeed is the issue.
LG appears to be suggesting that there may have been no feedback to a draft SAP.
But at the same time, he also appears to be suggesting that the new draft FDA guidelines somehow were a direct response to NWBO's SAP, or otherwise tailored for DCVax!
Is this at all credible?
Not for me.
I have no idea what 'four corners' means.
(A rectangle?!)
We already know that the tail is long and quite fat. Les will no doubt have more up to date blinded data than us that further confirms this.
But we don't know anything about delta and nor does he.
So how does he know the results are 'so good'?
He may end up being right that the UK approves first.
But at the moment, nothing is clear about the UK regulatory scene, given that we are in the middle of the Brexit transitional year.
If NWBO were submitting a marketing approval application right now, it would go to the EMA and not the MHRA, and be subject to standard timelines (be they the accelerated standard timelines or the standard standard timelines).
So while his remarks are not discouraging, right now I can only really take this as a piece of 'Les speak', with its characteristic hyperbole.
In terms of how it might translate into positive outcomes, I will take it with a very large grain of salt.
Prediction for the week.
Buying pressure all week.
Ave daily volume 4m.
Minimal profit-taking.
Week end between 0.55 - 0.65. I'll plump for 0.61.
PS. This is not a recommendation to buy!
Do your own research.
It'll get buried I fear.
Nothing must stand in the way of a vaccine.
I wish someone would wipe that smile.
Kind of like to think that our trial was just about over by the time that Covid-19 began affecting clinical trials, but it's an issue nonetheless.
"Quarantines,travel limitations, site closures or reduced availability of site staff" have been identified as factors that could lead to; "Missed or delayed visits or assessments, Loss to Follow-up, longer query response times, delayed site monitoring".
I think we probably escaped most of the issues, except possibly some hitch with last few queries.
https://onbiostatistics.blogspot.com/2020/
(Lots of other juicy stuff from Dr Deng on the same page by the way...)
What is this about non-intervention?
The Swedes had a whole range of interventions.
I can list them if necessary.
Anders Tegnell underestimated the percentage of the Stockholm population that would be immune by the end of May if he said 40%.
It's in the region of 95 - 98%.
This is comprised of those with innate immunity (nearly all children and most healthy adults). Included in those with innate immunity is those with genetic immunity.
Then there are those who have a robust t-cell response to viral attack, which kicks the virus out rapidly without the production of antibodies. Perhaps half the adult population. This group will be largely or completely without symptoms, though would likely test positive if PCR tested.
Then you have those with symptoms. These will produce antibodies, which would show up in serological testing. 90% of those with symptoms will recover without medical intervention.
Which leaves a small group who are susceptible to life-threatening severe viral infection.
The very old (with immunosenescence), those with co-morbidities that also weaken the immune system, those who are obese (particularly if they stay indoors a lot!), and those who live in deprived areas with high density housing.
Something like 40% of Sweden's deaths have been in care homes for the elderly. Because like nearly everywhere else, they failed to adopt the correct strategies to prevent care home infections, or to mitigate their consequences.
Why compare Sweden with the other Nordic countries? Geographical proximity has no bearing on relative CFR's.
Why not compare Sweden with other European countries such as the UK, France, Belgium, Italy, Spain, which all have higher deaths per million of population. All of which had lockdowns.
What is this about a second wave of the pandemic being expected in the Autumn? Expected by whom?
It is certainly possible that the countries with the strictest lockdowns will experience a significant (but likely moderate) 2nd wave after easing of lockdowns, precisely because those lockdowns artificially suppressed virus transmission. But that is just a very small part of the price of paralysing lockdowns.
There is minimal to no possibility of Sweden experiencing a second wave of deaths in the Autumn (mark this so you can quote me if I'm wrong, which I won't be!).
They will have a steady wave of new infections which will gradually permeate the rest of the country in the next 3 months or so. Most of these will be entirely symptomless. Deaths in Sweden will continue to steadily decline over the same period.
By the end of the year, Covid deaths in Sweden will have very largely ceased.
The various contact tracing schemes now being adopted in various countries will be completely counter-productive in any country where the virus genie is out of the bottle. In the UK, where perhaps 20-50% of the population have been exposed to the virus, exactly what is contact tracing supposed to achieve?
The UK has recruited an army of 20,000 contact tracers who will sit in call centres doing I don't know what!
Sending well and healthy people back into isolation is simply crazy.
S Korea did adopt rigorous contact tracing early enough for it to have noticeable benefit. But it's unclear whether continued contact tracing is sustainable even in S Korea. The recent example of one infective man visiting a number of gay nightclubs in one night resulted in 40,000 subsequent tests! It was hailed as a success, but actually just showed to me that such contact tracing is completely unfeasible in any country where infections past or present run at more than a few percent.
These apps will be introduced and then quietly dropped a couple of months later, when it is realised that they have a paralysing effect akin to the original lockdowns, for zero accrued benefit.
Secondary pandemic deaths are not easy to quantify. But in countries such as the UK, which simply stopped cancer and cardiology testing and treatment, you can expect unnecessary excess deaths in these illnesses to at least match Covid deaths.
And these deaths will be in a younger age demographic.
Economic decimation and the resulting long-term unemployment and new poverty, such as we will see in much of Europe and the US will lead to a huge toll of poverty related disease, deaths, and suicides.
Perhaps 5 - 20 times deaths from the virus in the next decade.
And countries / states with entire economic lockdowns will obviously fare worse.
I believe the US has lost 40m jobs since the beginning of the epidemic, with 20% unemployment now widely expected.
And when you look at life years lost, and taking into account the median age of Covid deaths, and the median age of collateral deaths due to the economic disaster, I would imagine that the impact of the latter will be at least 30 times the former. Probably much more.
Germany is a good case example of population wide disease progression. And a very good example of a low death toll due to properly resourced medical facility, and the competent exercise of authority. Less than one fifth of per capita fatality compared to a country like the UK. For Germany, the virus very definitely caused the same or less deaths than a typical flu season.
They have had approximately 8,500 deaths to date with a population of 83 million. Same virus as everywhere else...
And now their weekly death rate has dropped by about 80%, with very low deaths recorded in the last few days.
Small shops re-opened a month ago and all shops are now able to re-open, at the same time as pragmatic social distancing measures being retained.
Direct outcomes of the virus around the world will become more apparent in the next few months.
Indirect outcomes will become more apparent in the the next few years.
Vaccines are much more of a long shot.
2nd wave could be worse than the 1st
Steady on, BSB.
HL's thesis is a reasonable one.
Monday will show little to no change.
Have to disagree there Sukus.
It's true that countries like Brazil and Russia are now experiencing their first wave.
But pick any European country you like. Steady and persistent decline in deaths for at least the last month. Countries that have re-opened schools, workplaces etc, haven't seen a noticeable second wave.
Countries that had strict lockdowns may have a small second wave of cases, but those who were more relaxed won't.
Collective acquired immunity is now calculated to be reached after only 20% case rate.
This is because most with innate immunity (kids, and most healthy adults weren't susceptible in the first place.
Many European countries are already virtually there.
London's new cases and deaths have slowed to a trickle.
Continuing lockdowns simply prolong the agony, weaken immune systems and decimate economies into the bargain.
I'll stick my neck out and say a 'cure' will be unnecessary.