Mods and Rockers!

Anyone get me?

Austin

Do you hope I'm right or wrong?

Have you changed your trading position?

I said clearly at the bottom of my post that it involved conjecture and supposition.

Of course, it's your prerogative to make of it what you will.

Do you have an alternative viewpoint that you would like to express?

Amazing the amount of attention the ALL study that Jack brought to our attention, is getting.

It was the lead story on the BBC radio news just now.
The BBC pointed out that this was, as yet, unpublished data, and went on to refer to the serious side effects.

They then broadened their report to flag up the rapid advances in the wider immunotherapy field, and I suggest that this general heightening of public awareness can only be beneficial to NWBO.

Hi Jack,

Yes, amazing the news splash this story has made.

The Daily Mirror, a popular national daily (as you'll know Jack) devoted its entire front page to this story.

I haven't managed to work out which companies trial we're talking about here.

In relation to how this story has relevance to NWBO:
Well, they were talking about blood cancers, so not a directly
competing therapy.
The main study being quoted was for acute lymphoblastic leukaemia (ALL) with apparently 94% of terminally ill subjects going in to remission.

Impressive data.

Not so good on the safety side however. Of the 35 subjects, 7 experienced Cytokine Release Syndrome so severely that they required treatment in intensive care, and two of these died. This would indicate that their clinical trials are at a very early stage. A little surprising that the regulatory authority allowed the trial to complete with this level of SAE.

Can't help thinking that there is a very effective PR machine here, and that's something for NWBO to ponder on, in relation to how they disseminate their own publicity.

Hi Kabunushi

Yes, you raised the issue that I chose not to mention!

Suffice to say, that I believe Linda knows where the income stream is coming from, though I can't evidence it.

Plus, remember the veteran heavyweight Neil Woodford. He remains convinced about the science. It's still his intention to support NWBO right through to full approval for Direct in about 3 years time. After all, it's Direct that will turn NWBO into a Big Pharma company, not L, given its applicability to maybe 30 times the patient numbers, in comparison to L. He knows this.

Neil will not let any little public spat affect his investment strategy in any way. He's not that kind of guy. He is a true long, and as he has stated the (PhaseV anonymous allegations) are just a bump along the way. I expect he regrets making his public statement when he did though, as it has basically backfired on him.

So assuming the investigation finds that NWBO is guilty of nothing except the odd indiscretion (and that is my assumption), I expect he will resume backing NWBO in a couple of months. After all, that is the best way to protect his existing investment.

In what precise fashion he will do this, I'm not quite sure. I suspect he might resume drip drip investment in relatively small amounts, but enough to keep the shorts on their toes!
He, for sure, will lend his full support to the other investigation, the one that will identify the sponsor of PhaseV...

I also don't discount some form of government sponsorship for a number of cancer trials, nor do I discount sponsorship from a large charitable foundation. As well as the mercenary wolfpacks that abound, there are some powerful folks out there, that have genuine philanthropic intent, and a genuine desire to beat cancer.

L approval would also favourably change the picture, and institutional investors will rapidly jump on board. That might be 3 months away. It might be 18 months away. Difficult to say.

So that's my thinking and, yes, it involves lots of supposition and conjecture, but I don't think I will be a million miles away.

Why Phase 2 Direct has taken a bit longer.

It really doesn't pay to be cynical about this issue.

Instead, we need to try and see it from the companies position.

The Phase 2 trial is likely to enroll maybe 100-200 patients.

Quite possibly, it will be a multi-centre international
trial; US, UK, and Germany.

When it starts, recruitment will be very fast, as was the case for Phase 1.

Consider the logistics involved. Most obviously in respect of manufacturing. Guaranteed production capacity, Quality Control, cryopreservation and storage, supply and delivery systems.

All of these have to be in place.

Manufacturing requirements for L, will, of course, be continuing. And additional capacity is an essential requisite for L approval.

Final UK EAM approval granting, also requires all the above to be in place.

So, NWBO, by my estimation, has to double available manufacturing capacity this year. And then substantially increase it again after that.
Cognate will be earning its money.

And it is getting on with it!

Witness developments at Sawston, in addition to the production partnerships with Kings College and with Frauhofer.

Anyone with an appreciation of the above, would hopefully be less inclined to cynicism about delays.

Rk

I'm afraid you're off topic here again.
Tell you what, I'll let it pass, if you do the same!

Quote from your post:-


'There is also something called risk management. And putting any more than 5% of one's NPV towards any very risky endeavor (like options trading, or like investing in a micro cap bio with only one real product in development, having never completed a single controlled study with that same product, yet is nearing topline readout from their first ever controlled study) is foolhardy.

I have learned unfortunately though that many posters here and on the other boards have put much more than 5% of their NPV into NWBO. And at prices well above $5/share. I do genuinely feel bad for most of them. Not the sophists, though. Especially not the ones who advised them to buy above their own cost basis while maligning anyone advising otherwise.'

If I remember correctly, you used to frequently suggest 'put options' on NWBO.

And made comments like:-

'Investors should get behind this Company and its therapy. The data and regulatory validations speak for themselves.'

Actually, no. It would be more like:-

Placebo followed by L. Median OS 10 years
L followed by rest of L. Median OS 11 years

There is credible evidence to suggest that for
mesenchymal subgroup, L represents a 'cure' or at
least long-term remission.

So the above projection is not totally implausible.

The data would not fully mature for a generation..


I wonder, at what point the FDA would say 'OK, we've seen enough'

Just a small extract from the FDA's 'Guidance to Industry - Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics'

'Overall survival is defined as the time from randomization until death from any cause, and is measured in the intent-to-treat population. Survival is considered the most reliable cancer endpoint (my emphasis), and when studies can be conducted to adequately assess survival, it is usually the preferred endpoint.(my emphasis)
This endpoint is precise and easy to measure, documented by the date of death. Bias is not a factor in endpoint measurement. Survival improvement should be analyzed as a risk-benefit analysis to assess clinical benefit.'

Now that is great, because it avoids all the problems of pseudo progression.

Trouble is, apply that to L phase 3, and it will be a long trial:-

Placebo followed by L:- Median OS 4 years
L followed by rest of L:- Median OS 5 years

Now I am not joking.
I really do think that it could come down to something like this.
Mesenchymals will drag up median OS in both groups.

I wonder how the FDA would respond to such a scenario?

Where do you get 'sepsis' from?

There is no evidence that DCVax causes sepsis.

Really think you should withdraw that reference

Another reason why a patient would choose DCVax over Keytruda.
The excellent safety profile of DCVax.

I am sure I read that 38% of patients taking Keytruda have
to cease receiving it due to serious adverse side-effects.

'Compounds in lemongrass also have properties that might help lower your risk of developing cancer. Several laboratory studies confirmed that lemongrass components could prevent growth of cancer cells. For example, a study in the October 2009 issue of "Fundamentals of Clinical Pharmacology" found that citral from lemongrass slowed the growth of breast cancer cells in the laboratory and also caused them to undergo a process called apoptosis, which causes cell death. According to the Sloan-Kettering, components of lemongrass might also have a sedative effect, increasing the time you stay asleep. In addition, lemongrass may have anti-inflammatory properties that help suppress the activity of cyclooxygenase-2, an enzyme involved in inflammation that can cause pain in disorders such as arthritis, although these and other potential benefits still need further study.'

Well, what do you know!

You did some great analyses back in 2014, and I don't think
you get enough credit for them. I think you were really on
your game then.

Perhaps you could put up a few links for the more recent board members?

'Buy Lemon Grass, buy,buy!'

Your post suffers from the same problem.
Off topic.

Try and buy the rights to lemon grass tea??

Iwasadiver

You have to remember that Pyrr did a lot of work back in 2014
and strongly asserted that Direct was very effective.

I have compared his then analysis with his now analysis,
and personally I favor the earlier version, which stands up better to scrutiny.

I suspect in the next Direct trial, we will most likely see examples of temporary, apparent or pseudo progression, which will hopefully be followed by stable disease.

Proper trial design should ensure that trial participants do not leave the trial because of pseudo progression.

And yes, genetic testing, I'm sure, will be built in, including methylation status.

Thoughts on Direct Phase 1

It's ironic really that at the beginning of the trial, the FDA,
on the grounds of safety, only allowed 1 patient per month
to be treated, and that stipulation remained in place for about 6 months.
Regrettably, terminally ill patients with a life expectancy of perhaps
3-6 months had to wait maybe a month or two before receiving first injection.
With hindsight, it is not surprising that a significant number did not survive to complete the full course of injections.

And, the dosing regimen was very conservative, due to the fact that
treatment safety was being assessed.
Only one tumor injected, and injection intervals almost certainly too far apart.

When you bear all this in mind, it makes the long tail survival all the more remarkable.

Phase 2 will have none of these safety related restrictions and will be all about confirming efficacy.

As far as CI partnership goes, they should wait until Phase 3, and have one arm for Direct followed by CI.

After Phase 2 has unequivocally demonstrated efficacy, the CI companies (and the patients) will be queuing up.

When Pyrr discusses Direct, he starts from the premise that it doesn't work and only searches for data supporting that view. He knows that 50% of patients have 3 or less tumors, so makes several references to patients with only 1 or 2 tumors. He never makes reference to the other 50% who had 4 or more tumors.
He doesn't mention the delay of several weeks that many patients experienced before receiving their first injection. It is evident to me that a significant proportion of the patients were sufficiently advanced in disease that no therapy was going to help.
NWBO clearly made some gaffs with this trial. it was unrealistic for them to expect to see shrinkage of tumor within two months, when many of the patients were so ill that they did not survive to receive all injections.

Anyway just a reminder of Pyrr's thoughts on Direct, in Nov 2014 from Seeking Alpha, before he became a detractor:-

Quote:-
Steven Giardino, Contributor
Comments (548) |+ Follow |Send Message
Author’s reply » My take? Efficacy!
'The primary injected lesion in the ovarian cancer patient appears to have nearly halved in size. Also multiple other non-injected lesions "shrunk." It's a dramatic reduction from just 4 injections, 8 weeks into therapy (week 0, week 1, week 2 and week 8). The patient returned at week 16 to receive another injection, but first scans were taken. That is what they showed. It's quite remarkable, mid-way into the regimen. It also shows a stage IV inoperable ovarian cancer patient, with some 6 months to live, healthier at 4 months than in a long time, watching her lesions continue to shrink. And remember, this is only the first leg of the trial--in the second they will inject multiple tumors, which will likely increase both local and systemic effects.
The sarcoma patient saw his lung tumor increase in size at the 8 week scan (after injections at week 0, week 1 and week 2), but biopsies revealed necrosis and even bleeding. He was injected with his 4th dose at 8 weeks, and returned at 16 weeks for his 5th, but was first scanned. At that point, the 4 injections produced "extensive tumor necrosis and decrease in tumor size." This was likely the 28% reduction Linda Powers mentioned during the conference call.
At 20 weeks, one month later, he returned for examination (6th and final dose not until 32 weeks). Here they found even further necrosis and a slight increase in size, no doubt due to infiltrating immune cells and macrophages.
The process is longer than chemo but shows a natural, systemic removal of identified "foreign" matter--much in the way that a rejected organ transplant would eventually be destroyed and removed.
In short, it's working. And the beauty of the DC vaccine is it ADAPTS.. At each injection it takes on the exact expression of the evolving tumor. The DC's are at such a precise point in their maturity that they will take up any antigen sequence fed to them. This may continue ad infinitum theoretically, with no side effects to the patient. With multiple injects and possible reproduction of new vaccine (tumor samples aren't required), the patient could be given multiple injections causing tumor death and gradual shrinkage, all while creating a systemic effect like what is seen with DCVax-L. It's quite remarkable... I think we're witnessing the future in cancer therapy unfold.'
(My addition of bold type)

I preferred Pyrr's analysis before he went in to the 180 degree crossover arm!
So Pyrr what would you say now about your opinion expressed then.

Good find!

Rk

I wish you would read my posts properly before responding.

Some of what you have just said is paraphrasing what I have said.

If there had been talks between NWBO and BP, they would have been confidential and you wouldn't know about it!

If it does happen, then one day there will be a press release and you will know about! And yes, it might never happen.

I will take issue with you on one point:-

'BUT, as far as big Pharma being interested enough to partner is bogus.'

How do you know?

Do you have any evidence to support your assertion?

DoGood

Yes, very much agree with all that.

Regarding a possible partnership. It would be easy to advance an argument that BP have more to gain than NWBO from such an arrangement.

At the end of the day, it will only happen if both parties are convinced that it is in their individual interests to do so. If this is not the case, then it won't! Bit obvious really.

RK

Hello.

I didn't say that there was a part of your post that I didn't understand!

What I did do was correct this statement of yours:-

'But nope, no checkpoint inhibitor as of yet. Only mentioned a discussion a year ago. Nothing has become of it'

I referred you to the companies presentation of last month, where it was pointed out that two of the five conclusion points related to CI's.

So, it is still being mentioned, and the door remains open.

A question for you. What do you mean by 'they want to partner'?
Are you referring to the CI manufacturers, or are you referring to NWBO?
How do you know 'they' want to partner? Is this supposition?

Despite what you are implying with comments like 'I wouldn't hold your breath.....over a CI collaboration' I have an open mind about whether it is the right way forward.

I can see pros and cons. At the moment, I am just stating that it remains in the frame, and the fact that it was mentioned by NWBO only 2 or 3 weeks ago indicate that it remains in their thinking.

You have no idea what is going on behind the scenes. There may have been lots of partnership discussions between NWBO and BP. There may have been none. I have my own hypothesis on this.

Yes, of course it's a long road to approval, and yes two therapies will cost more than one. I think I had managed to work that out.

Whoever said it would be easy?!!!

RK. Not correct.

Please read the report from the Jan 26 presentation.
The link is on the home page of the companies website.

Quote:-

''DC-Vax Direct may help increase percentage of patients responding to checkpoint inhibitors.''

So, as I said to Austin, the idea of some sort of trial partnership, is still very much on the cards.

Pyrr

I think it is erroneous to suggest, as you did in your post,
that NWBO were specifically looking for an impressive ORR
in their Phase 1 Direct study.

Phase 1, as I'm sure you know, is primarily about safety
and dosing levels.

If you happen to derive some useful data, well, that is a bonus.

It's a little bit specious to compare Keytruda Phase 3 trial data, with Direct Phase 1.

Now, if you went away and dug up the Keytruda Phase 1 trial findings, then we might have a useful comparison.

Or alternatively, make the comparison when Direct completes Phase 3, and hard data is to hand.

Austin

Your post is not justified. You cannot imply that the reference to Checkpoint Inhibitors disappeared, never to be seen again.

At NWBO's recent presentation at Phacilitate on Jan 26 the slide presentation stated:-

'Patients treated with DCVax-Direct exhibit both de novo or increased T cell responses and de novo or increased PD-L1 expression.'

And:-

'DCVax-Direct may help increase percentage of patients responding to
checkpoint inhibitors'

So the door is still widely open.

DoGood,

I appreciate your post and concur wholeheartedly.

AVII. I'm afraid your response is flawed

In your post 53694, you quoted my previous post.

I stated:-

So the detractors of Direct appear unable to advance a plausible alternative explanation for the long-tail survival in the Direct study.
Your response was:-

''Easy. Subsequent therapy''

Well, the problem with that is, there is no available therapy that has demonstrated that degree of efficacy and ability to extend survival in
terminally ill cancer patients, such as those in the Direct trial. Can you think of one?

So, unless you can identify a miraculous therapy that might have been used, I consider your response to be without validity.

That is why Direct's potential is so exciting!


I will ask again;

Can you advance a plausible and valid alternative explanation for the long-tail survival in the Direct study.

Further in your post, you quote me again:-

Nor have they been able to explain that four or more injections correlates very closely with extended survival.

Your response was:-

''Again easy. Patients who live long enough to receive treatments live longer (any treatments; grapefruit juice or a miracle cure
cure). You (and NWBO) present an absolutely meaningless 'correlation'

I will disregard your insult to my intelligence and merely assert the following;

For patients who received four or more injections, the median OS, counting from the date of each patients last Direct injection,
is becoming more statistically significant as the data matures, and to me, is very encouraging and hints at tremendous potential.
No more, but no less.

Oh yes, when you stated that it must have been subsequent therapy that caused the long tail survival, I couldn't help notice your quote from Dr. Pazdur:-

''You cannot infer any therapeutic benefit of the subsequent therapy. It could be baseline characteristics. It's the old story,
responders live longer than non-responders.''

Well, blow me down! That is just what you attempted to do when you said; 'Easy. Subsequent therapy.'

The words 'hoisted' and 'petard' come to mind!

Yes Koman. Just how did CLDX manage full recruitment on a planned $60 mil spend, given that only a quarter of diagnosed GBM patients were eligible for their trial!
There could be all sorts of reasons.

So the detractors of Direct appear unable to advance a plausible alternative explanation for the long-tail survival in the Direct study.

Nor have they been able to explain that four or more injections correlates very closely with extended survival.

Yet, they still deny efficacy!



As a footnote:-

Necrosis v Apoptosis equals obfuscation.

We've been there, seen it, done it to death, about 6 or 9 months ago.

Can you clarify what you mean by:-

' I do believe it is helping somewhat for patients feel better, and hopefully that will translate to "provable" survival.'

and how that fits with;-

'DCVax Direct therapy as a mono-therapy is likely toast...'

And what do you mean by:-

'I imagine patients have moved on to other synergistic studies upon failing the vaccine and that could be helping. Again it could be doing something.'

The patients who had 4 or more injections i.e. didn't 'fail the vaccine' are the ones with long survival.

So you do not appear to have a plausible alternative explanation for the long tail survival.

Regarding the question of whether there is a crossover for treatment cohort on progression.
Yes, there is.
But only in a technical sense.
I believe that such patients would continue to receive the existing treatment.
For example, 5 injections, progression, 5 injections.
I do not believe that they could or would 'reset the clock' after progression.
Given the 'guidance for patients' statement that after progression 'You WILL be receiving DCVax' I don't think they can ethically use placebo after progression.
If they did 'reset the clock' then they would either run out of lysate or the patient might have up to 19 injections of L. And if they did 'reset the clock' and start giving L again at close intervals, they would be doing something that they had never tested in pre-clinical research.

RK
So how do you account for the longtail survivors in the Direct study?
How do you account for the correlation between number of Direct injections and the length of survival?

So Pyrr, are you unable to forward an alternative explanation for the long tail survival of Direct patients?

The greater the perceived potential of DCVax, the more vehement the attacks.
Best just to view them as backhanded compliments.

I was rather hoping you would elaborate.

So, can you offer an alternative explanation for the longtail survival of Direct patients who received 4 or more doses...

Have you considered that patients may initially progress (or pseudo -progress) and then go into relative remission?

For many patients, there is no doubting its efficacy.

Distinctions between necrosis and apoptosis just serve to obfuscate the fact that Direct represents a safe intervention that extends survival considerably. Quite by how much, we won't know until the data is fully mature.

Don't forget, median OS is the gold standard!!

Duckling

I'm afraid your post is nonsensical.

Well obviously I beg to differ regarding Direct as a monotherapy.

Really don't understand this comment of yours:-

'The funniest thing ever was NWBO trying to correlate shots with survival. They said (in effect) "patients that lived long enough to receive more doses than patients who did not lived longer." Awesome.'

What's funny about that?
It is born out by the trial.

Make a comparison with antibiotics. If you have sepsis, and you do not get antibiotics in time, or in insufficient dose, you may not survive.

The trial demonstrates that if you receive 4 or more injections of Direct, you will most probably be a 'longtail' survivor.

I can see a CI therapy being an adjuvant to Direct (not the other way round!) and, I imagine this might possibly be part of the design considerations for Direct Phase 2 trial.