Hi ILT.

I don't know much (if anything) about patent law. But I kind of think that if you have a complicated technology platform, that is almost impossible for somebody else to replicate by either guesswork or trial and error, then you may decide not to patent it, or at least not all elements of it.
It's almost as if the process of patent application draws attention towards your trade secret. And why would you want to do that?

Having said that, NWBO clearly think, or at least tell us, that they have a valuable patent portfolio that protects their platform technology.

I think there are layers and layers to this. You might patent an ancillary process that is part and parcel of your platform, perhaps to do with manufacturing technique (maybe like the use of tangential flow filtration?).
So you break down the whole process into several proprietary elements, and maybe patent some of them.

In practice, I think it is so difficult for a potential competitor to directly replicate NWBO's work, that few would even attempt to do so. They would still have to invest the hundreds of millions to go through the laborious and lengthy process of pre-clinical work and then the whole round of clinical trials.
We've have seen other clinical trials involving dendritic cells that don't succeed in trials and so fall by the wayside.
Which allows me to say; "They just don't have the secret sauce!"
And that is in effect true.
The secret sauce is in the process, not so much the biological starting materials. 'The process is the product' is the often quoted phrase.

Not that I'm totally complacent. And an employee who leaves a BP company, joins NWBO, then leaves NWBO and goes back to original BP company, makes me raise an eyebrow and ask 'what was that all about?'

With the notable exception of Car-T, BP really don't seem to be interested in genuinely personalised treatments.
They want products that can be produced in super large batches at the lowest cost and with the highest profit margin.
And certainly to date, the Car-T's haven't produced the volumes or the margins that BP are interested in. So they won't be in a hurry to repeat the exercise with, for example, a DC immunotherapy.

At the end of the day, does patenting fully protect your proprietary technology? Almost certainly not. But all the other factors make it very difficult for anyone to readily create copycat treatments.
Obviously the granted market exclusivity that comes with approval doesn't last forever, and varies depending on jurisdiction. But with an off the shelf pill, somebody else can easily create a generic version, after the exclusivity period ends. But this is not a pill. It will never be easy to reproduce or replicate.
That is certainly the case for L. Perhaps slightly less so for Direct.

Sooner or later, there probably will be another effective DC immunotherapy, but I think there is very little chance of it arising from wholesale 'borrowing' of all of NWBO's proprietary knowledge.

JMO.

Indeed, a supremely encouraging story.
I'm sure most know, but just to reiterate, he had two recurrences and it was after his second recurrence, when 70% of the tumor was removed and when he had been given a prognosis of just a couple of weeks to live, that he finally received DCVax-L.

Absolutement. There will be literally tens of millions of people around the world, who will have easy access to it, and will use it at the first sign of symptoms. Viral replication is blocked, the virus is cleared, and the individual never goes anywhere near a hospital, and will never be a part of a study. But that person will contribute (if tested) to a low case fatality rate in their own country. And the reaching of the herd immunity threshold.
What we have in the US, and UK is a policy designed to prevent the HIT being reached.
Complete madness of course.
Thousands and thousands of cases are good, if the standard first line treatment is in place. Because it won't lead to thousands of deaths. But it will shorten the epidemic. Sweden is just about there now. No masks! (Though obviously if individuals want to wear them, that's fine).
I think people generally are beginning to smell a rat as ever more ridiculous impositions are put in place and people see their lives destroyed. Are you ever going to re-open schools?

Nobody would care about it one way or the other if it didn't work.
Adding zinc as a companion will almost certainly help.
And really anybody who is the least bit aware will be using C, D, and Zinc already anyway, to boost their innate immunity.

The mechanism of action is really not a mystery, and this is a good description:-



Nothing must be allowed to get in the way of the fear, and the derailing and gradual dismantling of society as you used to know it!

I sure hope they are taking all the available lessons from the P1 and making provisional plans for a well designed trial for Direct.

But I don't want them to tell us anything about it. Because they will just end up making a rod for their own back if they do.
I doubt even a good TLD, will put sufficient wind in their sails to get things moving.

I'm a realist, and the chances are that Direct will have to wait until when and if L is approved. And that isn't going to happen tomorrow or the day after.

Unless they are successful in identifying a backer who really wants to get behind them and support them. And those type of investors don't grow on trees. But it's not impossible.

It had been on the backburner for years now.
And was probably taken off the hob altogether some good while back.
It's just that somebody finally got round to updating the CT site.
It's not really new news. I think we'd known for ages that it wasn't going to happen.
As such, I don't read much anything into it; good or bad.

JMO!

Must admit I'm not too keen on doing these FOIA requests, because I reckon they will want to know who you are and why you're asking, before they decide what, if anything they are going to tell you!

Obviously, this would be a fairly innocuous enquiry, as the lists are updated monthly and publically available anyway.

But a different type of FOIA might be about something they would rather not tell you unless they have to.
With the MHRA, it could be an investor or hedge fund trying to steal a march on the market or a competitor company or a journalist..

I like to do my research, such as it is, in a fairly anonymous fashion!

Regards.

Thanks Lykiri.
What I do is just check the monthly lists of new licensees.
Everything is available from here:-

https://mhrainspectorate.blog.gov.uk/2019/10/04/mhra-process-licensing-useful-information/

That was one thing that Les did say on that show.
Words to the effect of;- we can treat patients compassionately in the UK and we can get paid for that.
I know we basically knew that already, but it's just a bit of extra confirmation, if it were needed.

Now we could do with knowing whether Covid restrictions have lifted sufficiently to allow treatment under UK Specials to resume. As the 10-Q strongly suggested that Covid had effectively halted the programme.
I think your revenue estimate is a bit on the optimistic side, but obviously every bit of earned revenue helps.

It would be nice to know how close we are to a licensed Sawston. And that licensing process might be subject to Covid delay.
I think working out of Sawston would enable UK Specials numbers to go from very small to just small, with a corresponding increase in the revenue stream.

And treatment outcomes from UK Specials would also be very interesting, because they may be treating a wider range of patients than in the trial. Maybe rGBM, maybe other types of glioma, and maybe upfront DCVax-L in some case without chemorad beforehand.
All of which could provide them with additional insights into what works best.
Though I doubt we will actually get any such outcome data.
But you never know.

I didn't quote a company; I quoted an article that made reference to several companies.
It would be nice if you identify the company that you are referring to, and provide a link please.
Thankyou.

Apologies. Half the previous quote missing.
In full:-

Yes 8th June this year; 6 or 7 weeks ago.

Has something calamitous happened in Sweden in the last 7 weeks, that I don't know about?
The Volvo car plant re-opened back in April.
Of course there will be some supply line disruption, particularly for their heavy industry.
It's a global economy after all, and they won't be totally immune to the relatively much greater economic slumps in other western economies.

But do please tell me. What has happened in the last 7 weeks, that makes you think things have suddenly got worse?



How about a report from two days ago?

https://www.fr24news.com/a/2020/07/swedish-companies-profit-from-countrys-covid-19-approach.html

https://www.bloomberg.com/news/articles/2020-06-16/one-economy-stands-out-as-crisis-reveals-striking-differences

Of course the other thing about Sweden is for them it is over to all intents and purposes.
And no masks! Why aren't they having rampant new cases!
A total of 11 deaths in the last three days.

Schools open, shops open, restaurants open, all workplaces open.
Small GDP rise in Q1.
By rights, they should be well into a massive second wave...
Never a lockdown. Just sensible social distancing. No track and trace putting healthy people into quarantine.
Empty Covid wards. All other medical services maintained.

No traumatised kids frightened to go anywhere where other people are.
No state-engendered fear. No mental health crisis. No suicide crisis. No breadlines. No eviction crisis. No riots.

What happens in the US when the Covid financial assistance ends in 2 days?

How many countries do you want me to tell you about, meirluc?
I could give you a dozen links from a dozen countries.
The majority of affected countries in the world are using it, as first line treatment.

I will take a look, HFTF, but I don't really know how much more additional information they can give us about the P1. I thought the report we have both got was pretty comprehensive, including measures of PD-L1 upregulation, T-cell infiltration and cytokine levels.

Would be nice to know about any survivees, of course. But as a P1, long term follow-up was not an official endpoint.
It demonstrated all-important safety and that there were no dose-limiting toxicities.
And it established that Method B was better.

Don't know if you were around when they released the JTM interim paper. That got really good worldwide press coverage everywhere except the US. Some of the press reports are still up online.
Never seen anything like it before or since.

Whoever they used to get that out there, they need to do the same with topline, assuming topline is something to shout about.

But we already have the comprehensive outcome paper from the Direct P1.
I've heard several ask whatever happened to the paper.
But I don't know what people are expecting beyond this:-

https://clincancerres.aacrjournals.org/content/24/16/3845

(Thanks to Lykiri for putting the link up again recently.)

I'd have to review it to check whether he actually said it was the biggest killer. And if he did, it's patently false as you say.

He did go on about GBM being the most deadly. Which is probably not unfair. It's at least up there as one of the most deadly, though I'm sure there are some equally as deadly, such as childhood DIPG.

Yes, last I heard, all cancer approvals for EU member states go through the EMA. Though that doesn't bother me particularly; it's just sloppy rather than intentionally deceiving.

The thing is, on a pay to play platform like this, he knows the hosts are going to lap up everything he says in an entirely non-challenging way. So it really is advertising without any of the consumer safeguards that apply to normal media advertising.
I take it you have some safeguards or codes of practice for TV advertising and the like. Even if they are pretty lax compared to elsewhere.

Who is this show aimed at? Presumably it's the investment community (whatever that is..).
I don't honestly think it would influence potential institutional investors, because they would recognise this show for what it is; a plain old infommercial.
I'm sure that young lady with the instant blood test (my minds gone blank) went on shows like this. Theranos, that's the one.

So if it's aimed at anybody, it's probably private investors like you or I. Sorry I meant just 'I'.
Unless this show encouraged you to put your hand in your pocket?
And I think the answer to that is clear...

So really, it's just a bit sleazy in my mind.
And as well as being a bit sleazy, I'm not even sure this sort of thing is value for money.
It's interesting to us, because we can parse every single comment he makes for insights into how he thinks and operates, and maybe get some pointers into company intentions.
But there's an element of preaching to the converted.
Maybe it gets some new retail on board, I don't know.

Which brings us to the stated intent to go straight for regulatory submission asap.
Can we take that as a 'will happen'? Not really, imo.
Because he made that comment, does it make it any less likely that topline might be somewhat equivocal, with some hedging of bets in the way they PR it?
I don't think so.
Obviously I hope they do have a coherent SAP that has at least been run by regulators, and they know how they will apply the data to the SAP and convert that into a BLA without delay. And if that's all in place, then we will get a very definite and positive topline (assuming the data itself is up to scratch).
So really, I just take it as an infommercial. And a very far cry from a full data exposition at a Conference with a critical audience looking on.
I preferred Les when he stood in for LP a few years back at that professional conference when she went down with a bug (early Covid adopter?)
And he didn't do too badly back then, all things considered, even if he couldn't pronounce 'precursor'.

I also found myself wondering if he dyes his eyebrows.

Well, he really ought to say 'if the data is positive'.
Because he doesn't know yet!

Hi hyperopia. I have enjoyed many of your contributions, by the way.
Thanks for the link. Yes, I've seen it, but not in recent times.
So it's good to have a refresher.

I would say this falls a little bit short of actually explicitly declaring that shelf-life is fully validated to the satisfaction of regulators for 5yrs or more.
I'm coming from a position of half-expecting regulators to come up with 'issues' possibly somewhat spurious, or 'seeking confirmations' or nitpicking queries at any stage. So sometimes NWBO might think that they have already demonstrated something to a high standard and to regulator satisfaction, only to then find the regulator looking for even more in the way of confirmation. So I think that this might be a process in play at every stage. And I have the BLA in mind as something that, however rigorous and exhaustively comprehensive their application is, the regulator will find something requiring them to go back and compile additional information for submission.

I'll happily acknowledge that shelf-life might not be the issue at all. It's just a possible for me, and I don't have any particular investment in the idea.

And maybe spending time on trying to identify the reason for the partial hold could be seen as a bit of a fool's errand anyway, because where does it get you, when you want to have a basically forward-looking perspective?
On the other hand, trying to second-guess what might be going on behind the scenes on any issue or at any time and doing a bit of dot-connecting might add to one's own subjective investment hypothesis. And you don't have to influence or persuade others, when you are just developing your own hypothesis.
Which is different to concerted pumping or its opposite.

It's part of the fun I guess, just to share ideas and debate with others.
Speaking of which, do you have any thoughts on the hold?

Yes, I thought I was on safe ground saying that...

But, if they learn from experience and get the trial design right and pick the right endpoints and avoid clinical holds, I think 5yrs from today is not unreasonable. Recruitment will be fast especially if they opt for a single arm. These are going to be late stage patients with very few options. They probably won't be able to get to first line until a few years after that.
Let's be honest, if the regulator backs them like they did the Car-T's, then it definitely realistic. But that is a mighty big 'if'.
Does P1 to P2 to P3 really mean anything these days? Don't think the Car-T's ever had a P3.
And something else was approved after a Phase 1(b)!

Of course all this is dependent on L approval. But if they achieve that, I think, one way or another, the cash avenues will open up and the runway will be clear. At least to start with.

I was thinking about what they might use as a surrogate, so as to stand a chance of AA. And as you know, I don't like Objective Response Rate after 5 mins of treatment, because of how it doesn't correlate well with survival. And I honestly wouldn't want Direct (or L) approved, if it wasn't justified by solid evidence.
Maybe they could go for something like ORR at 12 months? As well as OS at OS12 and OS 24.
ORR at 12 months would take them past pseudo-progression hopefully.
And the last thing they would want is another goddamn trial with results muddied by pseudo-progression!

And maybe some sort of basket trial with smallish numbers of different cancers.

Just thinking out loud really.

Lykiri. Yes, it may well have been that patent application. Or their might have also been another paper.

But that is great, and thanks for finding it. Duly bookmarked.

Dangerously close to describing trade secrets, so I think we take note of it, but not discuss it too much!!

All the delays in Direct thus far have simply been down to cash. Very regrettable, but also true.

I never suggested Direct approval would be easy or fast. In fact I gave a reason why it might be quite hard in practice. I did say that I believed Direct active trials should just follow on, if L is approved. Because I believe that L approval is all the affirmation they will need for the financing avenues to open up, and the runway to be clear.

But fast? Fast is relative.
Fast compared to L? Most definitely.

'Totally different programs'?
I would call them related programs or even closely related programs.

I predict there will be nothing in topline and nothing in full data presentation about mesenchymal. Nor will there be anything in a BLA about mesenchymal. Nor, in my opinion have any of the trial subject's samples been through genomic analysis, so imo they don't even know which patients are mesenchymal. Or were mesenchymal at some point, or were pro-neural but later became mesenchymal. Or classical. Or classical then later mesenchymal. Or had a tumor with bits of pro-neural and bits of mesenchymal. Or bits of classical and bits of mesenchymal.
I'll stop there.

But each to his own opinion.

Thanks, Lykiri. This was the other paper that I had in mind.
And I will now bookmark this one. This one is like the official P1 follow-up paper reporting outcomes and findings.
But the other one I was referring to, went into more detail about the critical maturational time period. It even said something like 24 hrs was too long, 18 hrs was just right (or something similar). It was basically describing how Method B was better, but the paper didn't call it Method B. I don't even recall who the author was.
Possibly not Subbiah, maybe Bosch.

I don't think I dreamt it! It's out there somewhere, unless they took it down for fear of revealing trade secrets...

But thanks for this one.
If anybody can find the other one, you can!

I would say they are similar in principle. Use the maturational cocktail to optimally mature the dendritic cell pre-cursors that come from the PBMC's from the leukapheresis.
Though this is more time critical with Direct so that you derive 'adolescent' dendritic cells, that have both migratory capacity to lymph nodes and also antigen presenting abilities.
And it's incorrect to say that Direct 'uses none' of the tumor antigens. It uses all of them, at least theoretically.
It's just that with L the antigen presentation is in vitro and with Direct it is in in vivo. But the fundamental principle is the same.
There is no guarantee that they will have equivalent efficacy.
Direct may elicit a lower response rate than L, or it might actually be better. Who knows?

Direct manufacturing is simpler due to only having the one autologous component and not two, and that is probably why Direct is more amenable to closed system automated manufacture. Which will likely make it cheaper to produce, and possibly a cheaper therapy.
I think everything is more time critical with Direct, because the intention will always be to administer it asap after manufacture.

There is a detailed paper floating around somewhere that came out of the Direct P1, which went into quite a lot of detail about how they had learned the time critical partial maturation, which they had previously referred to as Method B (for better).
And I remember thinking that they were in danger of giving their secrets away in that paper, because it was so detailed.
But I've lost the bookmark somehow.
Don't know if anyone knows the one I'm talking about, and can perhaps put up the link.

It's somewhat moot as to what extent an approved L could be used off-label. I don't see why it couldn't be used in other cancers wherever there is a tumor resection, if the responsible physician believes its use is justified. Though that might be pushing off-label discretion a bit far.
For sure, I think it could be used off-label for any type of resectioned brain tumor, not just GBM.

Yes the first Direct P3 would take a while, and you would come straight up against a single-arm versus a randomised study dilemma.
Randomised would bring up all the ethical issues of denying a control a potentially life-saving treatment, and injecting a tumor with a placebo??
But with a single arm, how do you get a control comparison?
So trial design would be critical to ensure that you get a speedy outcome that gives you data that warrants approval. Would Direct be granted the same smooth passage as the Car-T single arm studies? I very much doubt it.
I loathe tumor response rate as a surrogate for OS, but if they wanted AA through interim analysis, that is probably what they would think of using.

Think you're being too negative about this. If L is approved everything else should follow, if a level playing field exists.
The resistance and obstacles would come from the status quo, that would recognise Direct as a big challenge to the established order in cancer treatment.

Just opinion.

Hi Senti.
Yes, I recall seeing that.
I ask myself ; what does 'more than 3yrs' actually mean?
And really, I think it only means 'at least 3yrs'.
Maybe they did a viability test that got to 3yrs and a couple of months, but no further.

If they had validated a shelf-life of 4yrs or just over, to the satisfaction of three regulators, then I think they would have said; 'more than 4yrs'.
So I still think my shelf-life theory is a possible (as reason for hold), though I'm not at all saying it is the reason. Rather it's just one of the more likely theories for me.

And I haven't discounted the whole 5-ALA fluoresced tumor tissue issue as another possible reason. They might have been required to do extended testing to demonstrate that L made from fluoresced tumor had all the same critical quality attributes as that made from non-fluoresced.

Again, just a possibility.
But on this one, if during the hold, they had scientifically proven by testing that fluoresced tissue was just the same, then although a pain at the time, it would have been very good to prove it during the trial, and before BLA or approval, so that after approval there is no impediment to treating patients who have 5-ALA surgery. And 5-ALA surgery might well be on the way to becoming the norm.

I know there are more positive theories about the hold (and more negative!), but I think my ideas fit the likelihood best for me.

Regards

Hi Abeta. The thing about GBM tumors is that they are constantly morphing between the different cell types, especially as a result of treatment challenge, whether it be chemo or rad or anti-angiogenic (Bev). And although the shift is basically towards mes, it can also back-double if necessary.
It's why I don't really buy in to the 'DCVax works best with mesenchymal' thing.
Rather (for me), it's the only thing that works with all types.


Here's a quote:-

https://discoveries.childrenshospital.org/glioblastoma-single-cell-sequencing/


I like to think that L is the only therapy that can target all four tumor states at once. Especially if the autologous whole tumor lysate (from which the L is made) has that full cell heterogeneity. And the tumor cannot mutate to escape, because L has all the bases covered.
That's my lay person way of understanding it.

And hopefully there is a simple key to achieve similar efficacy with unmeth also, if they can only find it.
(I don't think it will be using an ICI...)


Regards.

Yes, maybe they will be able to get the meth status of a few more subjects with all these assays they are undertaking, though I don't know the technical possibilities.

Subgrouping by meth status was pre-defined, and it is by far the most significant biomarker. So if they can ascertain for a few that were previously unclassified, that would add a bit of stat strength to that classification.
Not sure what you mean by classifying by subtype; whether you mean meth status or genomic subtype.

I do believe you are right. They are telling us that all the subject clinical data has been collected, all queries resolved, basically all scrubbed and ready, and now resides in a locked state with the CRO. That should include everything that pertains to endpoints, and also the record of SAE's (which hopefully will be a very good record rather than anything of any concern). So the company (and hopefully nobody else!) will have cause to access that database until full unblind.
I get the feeling that they've basically achieved what they previously described as soft lock, but also that they've decided that it's not worth accessing the data on a soft lock basis. So they are just leaving it tucked away and not touching it.
And they are just shy of full 5yr data for the last few patients.

Basically, all that appears to be left outstanding is patient biomarkers.
And the one we know they are trying to collect is IDH status. I don't think they are going to be able to gather this 100%, because I suspect that there may be no available tumor tissue for many of the subjects, particularly for those who were in the early years of the trial and are now deceased. In the last few years, screening for IDH status has been standard practice for most all GBM patients anyway, so for some later entrants, they may already have it. The way I read the PR, it sounds like they may even be going back to some currently living patients to gather fresh samples, but I don't really know how they would achieve this (liquid biopsy?)or even if it is biologically possible. I think there are several different assay techniques to ascertain IDH status, so they may be using more than one in the case of some subjects, to get a confirmed result wherever possible.

The question that comes to mind is; why didn't they collect this as they went along, as part of patient screening. Well they perhaps couldn't do it for early patients due to the role of IDH mutation in GBM only being discovered in about 2009. But IDH status may have been routinely gathered for some of the late entrants, so they will already have some of it.
I tend to think this is a regulator request made in just the last year, which has necessitated them having to try and retrospectively gather this information for as many subjects as they can. Bit of a pain really, because it is unlikely to alter trial outcome in any substantive way, but it could be seen as academically useful. I don't think they are chasing down any other biomarkers, except possibly EGFR amplification. Which again isn't of much significance in the scheme of things.
I really don't think they intend or are even able to identify the different genomic transcriptions, such as pro-neural, mesenchymal, classical. And these latter classifications are a very moveable feast anyway, due to intra-tumoral heterogeneity and shift over time.
So on IDH, they will try and get a status confirm wherever possible, using maybe a couple of different commercial labs, but they will just go as far as they reasonably can, rather than chase forever.

I can't see any other unexpected hold-up, so I'll stick my neck out and say we will get confirmation by PR of full datalock, not later than the mid-point of August. And I do think they will publically confirm it.

JMO.

You said datalock is imminent.
Then you said they are waiting for 5yr data.

Which is it?

Oh dear, Ex...

Scotty. Haven't you finished feeding the lawn and mowing the cow yet?
We're missing your input....

Not quite yet....
When they finally can datalock; then they will be.

Many a slip 'twixt cup and lip.

All the delay is down to Covid and third parties. Not NWBO's fault.
As I told them to do; just keep us informed in detail every two weeks. Market can handle that; quite likes it in fact, as we see today.

Though this update was about a week overdue.
Silence is enemy of share price.

I reckon they will PR data lock, because they will want to express their own relief, and I will join them in that relief.
The rest will just follow, because things will be back in their control.

Not that important.
Primary GBM's are almost always IDH wildtype. Likely 90-95% of the trial.
IDH mutations are hallmark of secondary GBM.
Only a few percent.
As Senti says, they just need to show that they didn't artificially stack the trial full of secondary GBM's. Which I'm sure they didn't.

My guess is that a regulator asked for this late in the day, so NWBO have to oblige.

All good. All as expected.
It's going to happen, albeit a bit late.
Now I'll go back to sleep.

Like your style, Marzan!

0.35 is the new normal..

Still, better than 0.17.

Two 'c's in flaccid.
Just sayin'...