Roundtable Discussion; The Future of Mineral Sands. Watch the video here.
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Bella
Agree with all your points but we will only know when arm2 results are analysed
Targetting directly into the tumour reduces damage to other organs, nasty side effects and allows for higher dosing...
The first too add huge value for patients...the latter if it leads to faster cancer cell death is a huge bonus.
What is not to like...?
One in Two get cancer nowadays...derampers are not immune and to try and take down a company try to find a better method of administering these very toxic chemo drugs is not a good look...
Blaming Avacta for your own investment decisions is soooo dumb...
I refer you to my posts after the December briefing in which I questioned rate of AVA6000 cleaving versus rate of cleaved fox being excreted. The AVA6000 half life in the bloodstream is very short. I said that I thought the variable results in patients was a strong reason to delay P1a to insert a 2 weekly trial in the expectation that this would improve results to the extent that BP or IIs would be convinced enough to invest.
The Pom Pom girls poo pood this suggestion but I still feel that this was the main reason for the change in strategy. I think and hope that arm2 will give us the results we need but it is far from being a slam dunk and that is why we are where we are.
Al is the king of the ambiguous communication especially if it allows him to big up the prospects of Avacta. You have only yourselves to blame if you chose to read Al’s words in the best possible light and then over invest.
Clearly: more ava6000, more cleavage, more dox, more cancer cells disrupted
I’m sure: if any competent scientist were performing a trial, they would ensure that the data collected would inform them on the effects of increased dosing. Such as the half life of the dose. They wont be making decisions in a vacuum.
Not trying to win any arguments here, just trying to make logical sense of it all.
'Clearly' and 'I'm sure'.
That's an argument well won then Gje.
Clearly increasing dose frequency will increase the efficacy, and they can keep on increasing the frequency beyond 2 weeks exactly because it has been shown to be safe. I'm sure they have already calculated and identified that 2 weeks will deliver the results they're after. Once approved, all other combinations can be tried out by clinicians as they build up their knowledge of this drug.
As for the backers... we had first hand evidence that there are plenty who backed the raise with absolutely no clue of the underlying science.
Yes a half life extension process should make it better (?)
But is it good enough without it.
Who knows?
Well, I suspect they do.
And those who backed the raise.
At 50p.
I'd say most of it is excreted, given the half life of ava6000, but that's not the important bit here, it's actually how much is converted and concentrated in the tumour, and the answer from the biopsies is there is enough to be therapeutic. The excretion of the majority of it is a necessary part of the process. If you consider that in order to get a sufficient concentration to the tumour through the bloodstream, it is a requirement to raise the levels of AVA6000 throughout the body. Only the AVA6000 that happens to pass by the tumour will be cleaved. The excreted AVA6000 represents all the dox that would otherwise be absorbed by healthy tissue, so it's an overwhelmingly positive thing.
Roll on the half life extending serum they're working on and one can only imagine the boost to efficacy.
They must know what percentage is excreted unchanged (dose administered minus 'leaving group?).
A question for next week?
I await your reply.
Because straight Dox is excreted as straight Dox Alberan.
AVA6000 Dox might be excreted as AVA6000 before it gets a chance to 'meet the tumour' and do its job, to be released in the TME after which it should be excreted as cleared Dox, because that's what it is.
But it starts as uncleaved Dox.
What percentage is excreted uncleaved Alderbaran?
Do you know or was your post one of those one liners that imply certain knowledge?
Apologies if you're a Professor of Oncological Pharmacodynamics.
Are you?
There's a lot of science here Gje and we're all allowed an opinion.
I'm inclined to think that AVA6000 will prove to be rather good in the right patient groups and Avacta will do very well.
I'm planning to invest accordingly but I don't trust posts that contain certainties and absolutes, you've only got to read the majority of posts to realise that most have made their mind up and are completely deaf and blind to any changes that might have occurred along the way.
Thanks for you in-depth and detailed posts though and lets hope that there's a bit more to help guide us during next weeks presentation.
Thorn.
Why would cleaved dox behave any different to straight dox?
I'll wait
They were taken 24h after the dose of ava6000 was administered - see here: https://avacta.com/wp-content/uploads/2023/02/MASTER-DECK-Avacta-Science-Day-23.02.23_compressed-1.pdf
I suspect that any dox cleaved by fap will be absorbed in the same way as straight dox and so will have a half life of 20-48h before being excreted, although it's not stated whether this applies to tumour tissue as well.
I can see a dosing regimen where dox to the tumour is topped up frequently so as to counter this half life excretion and maintain the assault on the tumour cell division, as working well. I'm sure that Avacta scientists and the clinicians involved are all itching to try these various approaches and it's just the reality of business, time, resources etc. which are limiting this to 2 weeks, with the focus remaining on getting this through and approved.
Thanks Gje.
How long after AVA6000 administration was the tissue biopsy data taken?
If AVA6000 is indeed flushed from the body rather quicker than anticipated (I'm not a mouse) does that mean that elevated tissue levels are also rather transient?
Do you know?
Are you offering a Guarantee Certificate that tissue levels are maintained and that the total Area Under the Curve is sufficiently high to do the job.
Because I don't know, unlike BV who appears to think he does.
Sheppy aka wynbore sptop looking a twat
Thorn, the mouse models, biopsies etc. have all show us that the mechanism is working, so this means doxorubicin is getting deposited in the tumour and in sufficient concentrations to start killing tumour cells. The did provide us with the values in the science day. So this much we do know.
The independently defined therapeutic thresholds for the various mechanisms of action were listed in the science day slides as:
Doxorubicin Target Activity DOX IC50
DNA adduct formation 1 25nM
Free radical formation/cardiomyocyte apoptosis1 100nM
Topoisomerase Inhibition1 400nM
In vitro cytotoxicity2 30nM-3µM
Whereas, biopsies were in the range 79-2419nM.
This doesn't tell us what the values would be for straight dox, I agree.
It is true to say that straight dox is sucked up into the cells rapidly, with an initial half life of 5 minutes from tissue absorption alone. Once inside the cells they do their damage, both to the tumour cells, and to healthy tissue around the body. Essentially it is cells currently undergoing division are targeted by the dox (this is the most significant mechansim). Once inside the tissue there is a longer terminal half-life of 20-48 hours.
So it's probably safe to say on a like for like dose more straight dox will reach the tumour in the concentrations in which it is administered. However, you are also killing the person at the same time, which is less than ideal. You are also restricted to 3 weekly dosing due to the damage caused by the non-targeted distrubution of dox around all tissues.
Now considering the mechanism of action whereby only dividing tumour cells are actually destroyed by dox, and that only a subset of cells are dividing at any given time, the efficacy of administering straight dox (all other pharmacokinetic considerations aside) is limited by:
1. the number of dividing cells that can be targeted before dox is fully excreted
2. the growth of the tumour between the time the concentration of dox has dropped below an efficacious dose and the next dose can be administered
3. the time that has to be elapsed before a patient can receive another dose
Clearly if 2 is greater than 1, then sadly the tumour continues to grow (albeit more slowly) and the patient is very very sick from the doxorubicin alone.
Now compare the above to precision. Given that no mtd has been found yet, clinicians are free to adjust:
a. elapsed time between dosing
b. duration of a single dose ie. the rate it is administered
c. the maximum concentration of a single dose
all in the knowledge that healthy tissues are spared. Given we know there is already a therapeutic concentration found in biopsies, it is clear in my mind that if the dosing frequency and concentration are optimal, the clinicians will be able to ensure that dox can be administered to the tumour at such a rate that 1. (above) is greater than 2. and so the tumour begins to shrink.
This is all premised on the tumours being high fap and having
Truly don’t understand trolls lol
Why waste breath
It works ?
Doxorubicin can be dosed weekly, but at a third of the 3-weekly dose, 20 vs 60.
https://pubmed.ncbi.nlm.nih.gov/3786819/
Sub optimal?
Lol
Try dosing red devil every 2 weeks and see what happens. AVA6K being doses at over 4x max allowed dose of red devil and no mtd found.
I repeat no mtd found.
Chat all you want about management and funding and cln blah blah but the science works and trial going exceptionally well.
Still expect 38p in short term but long term many pounds
Don't worry Thorn, the CEO will shortly dispel all doubts with a "we'll sell all we can make" comment or how about "you don't need to worry about funding" one. This is AIM folks, wake up and smell the coffee and ask yourselves how many board members bought in the recent raise.
Have you been given a Guarantee that it works BV, by which I mean AVA6000 is clinically effective and equal than or superior to standard Dox?
And yes it's a delivery platform but they've switched to a 2 weekly dosing regime because the 3 weekly schedule is thought to be sub-optimal presumably?
So they're hoping that the 2 weekly schedule will prove to be more efficacious?
So doubts then? No guarantee given? Might be being flushed from the system too quickly to be clinically effective. Which would might affect the prospects of Pre|Cision as a delivery platform?
I wouldn't dream to suggest that it wasn't effective but I'd be equally cautious about saying that you were guaranteeing that it was?
BV. Re ‘ deals’…
Only ‘ concrete info’ within Commercial Director appointment RNS…’ interest expressed’.
Plus AS chatter.
GLA
Why do you think partnerships are a long long way away and that there's no guarantee still that the science works Rob?
You've made the statements, so justify them and enlighten us please.
Or hide and be filtered by everyone with any sense.
And then you woke up