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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 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.

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.

Careful what you wish for indeed. HE1 replaced their CEO and the new one (Lorna) duly sold every single existing shareholder down the river to the tune of a 95% dilution. Effectively gave the company away to the spivs.

I'm more supportive of retaining AS but surrounding him with the right experience for this phase of the venture.

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.

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

Honoured.

It's looking like the SP is struggling to get back above the support line that Zak Mir pointed out. Would it be sensible wyndrum, to take a bit off the table, just to hedge against the possibility of a 10-15% drop from here that you have suggested?

And no concerns over AS's honesty and ability to execute as CEO, wyndrum? What is the catalyst for a share price rise in the coming months, what is going to stop this falling lower?

Wyndrum, any concerns about the convertible bond dilution over the next 12-24 months?

So let's get this straight please wyndrum and aldebaran, is the share price going to rise from here? Does this mean we're well and truly out of the death spiral scenario, and Alan Smith is competent once again. I was under the impression that we need to dislodge him. How does this work - last week we needed to get him ousted with pitch forks?

Thorn - help me out here?

The dilution is going to be massive over the coming months. I can even provide the numbers for conversion of the bond at 10-20p to back this assertion up.

Thorn, want to see the numbers?

At the start of this rise back in 2020 i.e. it hasn't been filled in yet - and it's a big gap from 23-29p. If we get anywhere close to it, the gapitational forces will be strong.

Not after they have consigned dx to the footnotes of history, or should I say, website?

95% of all gaps are filled, plus remember the convertible bond death spiral that Thornogson kept going on about, that will definitely drag us down to 20p.

Isn't that right Thorn?

Over the coming months there's going to be massive dilution and it will provide downward pressure all the way down to 20p, maybe beyond?

It has to fill the gap at 23p, at which point I can buy a shed load and make a mint.

The mechanisms employed, namely the conversion bond and raising exclusively with II’s at a huge discount (bar throwing a bone to long termers) supports that argument that they are reshaping the register. However, I don’t necessarily buy this given some of the “diamond handed” II’s that we saw participated. In addition, we’ve not seen a single tr1.

Nevertheless, this is still bargain territory and whatever the ultimate reasons for the raise, buying down here is still better than buying up at 160 by a factor of 4.

Can you explain why a free float will do that? What’s the financial mechanism you have in mind which sees one scenario as preferable to the other?

This time, PL75, the goal has been brought to Alan. The ball has been placed on a tuft of grass, and all he needs to do is swing a big left foot with enough precision to make contact with the ball. Then we score. What could possibly go wrong?

It helps to set the context to understand the perseverance required to succeed in this industry. Avacta have many talented people no doubt, but they are not immune to the statistical reality. That they have failed to see through a number of ventures to date is not unusual.

Precision hopefully is different and will represent the breakthrough venture that Avacta desperately needs. Not sure where they would go from a failed precision trial tbh.

Many drugs are flogged through trials on the promise of very marginal improvements over current treatments and yet we are seeing the precision trial is already yielding some pretty top end results. Now it is funded, I'm more confident that finally they can see this through through to commercialisation.