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I think the buy price has largely been below the midprice and so buys have been showing as sells.

I'm expecting two things on Science Day: an update on Avacta's therapeutic programmes (from Avacta) and putting the programmes into the context of oncology now and future (from the KOLs).

There isn't enough in the public domain about the current status of Avacta's therapeutic programmes - WHAT?!!! No developments in the last year or two?!!! - to make a Science Day that is "an update on the ongoing preclinical programmes as well as on progress in the ALS-6000-101 phase 1a clinical trial of AVA6000" without an RNS beforehand, so I'm expecting one to put some flesh on the bare bones of the RNSs over the past couple of years.

The talk from the KOLs will be for the privileged ones in the room.

Like with the AGM, where we got the slides for the day in a link from an RNS, I'm expecting those in the room to get a lot more from the day than we'll get in any recording of the day, which could be selective or very long.

Wouldn't it have been better to livestream the whole thing? Maybe no if those in the room are going to get some 'extras' - an incentive to attend.

I'm expecting two things on Science Day: an update on Avacta's therapeutic programmes (from Avacta) and putting the programmes into the context of oncology now and future (from the KOLs).

There isn't enough in the public domain about the current status of Avacta's therapeutic programmes - WHAT?!!! No developments in the last year or two?!!! - to make a Science Day that is "an update on the ongoing preclinical programmes as well as on progress in the ALS-6000-101 phase 1a clinical trial of AVA6000" without an RNS beforehand, so I'm expecting one to put some flesh on the bare bones of the RNSs over the past couple of years.

The talk from the KOLs will be for the privileged ones in the room.

Like with the AGM, where we got the slides for the day in a link from an RNS, I'm expecting those in the room to get a lot more from the day than we'll get in any recording of the day, which could be selective or very long.

Wouldn't it have been better to livestream the whole thing? Maybe no if those in the room are going to get some 'extras' - an incentive to attend.

I haven't got a clue. I don't make SP predictions.

https://twitter.com/i/status/1212317920593924101

And another interesting thread becomes a pointless pile of merde. Well done BOTH.

One important point to emphasise is that the permeability of AVA6000 through the TME is in no way related to the permeability of doxorubicin through the TME as the former is inert until cleaved by FAP and the latter is active from the start with rapid uptake by proximal cells.

This work tells us that doxorubicin has decreasing activity the further it is from entry into the (tumour) tissue. I'd suggest that that is good for AVA6000 if the doxorubicin can be cleaved off in the TME, which is what the data we have so far say.

My musing on this:

Both standard doxorubicin (D) and AVA6000 (AVA) circulate in the bloodstream. Both cross over into tissue indiscriminately (note that AVA is not targetted to tumour tissue).

D starts working immediately and is used up as it permeates the tissue. One can assume that the type of tissue, whether cancerous or healthy, makes no difference. AVA is inert until it encounters FAP; if there is no FAP in the tissue the AVA will diffuse back into the bloodstream (note that this should mean an extended half-life in the body).

AVA is cleaved when the tissue it has reached contains FAP (the TME); the dox then goes to work and is used up (little or no leakage back to the bloodstream).

If a) AVA permeates the TME, then dox can be released anywhere in the TME; if b) it doesn't, then dox will be released in the outside layer of the tumour 'onion' and will be used up there, similar to how D works.

In the case of (a), a large bolus dose could be given to zap the tumour. For (b), a slower, more dilute infusion or smaller repeat infusions could be given depending on how quickly the outside onion layer of dead tumour cells falls away exposing a fresh onion layer.

I had mused about this earlier:

RE: “If it wasn’t activating, would tolerability be an issue?”
24 Nov 2022 10:59

...

Factors to consider that affect the 0%-100% inert-full activation range will include:

1. The infusion concentration and rate of administration (e.g. in mg of AVA6000 per minute) - i.e. concentrated over a shorter time or diluted over a longer time.

2. The capacity of FAP in the TME to cleave AVA6000 (e.g. in mg per minute) - i.e. FAP's natural rate of cleaving and how far into the tumour AVA6000 penetrates (a concentration profile in the cross-section of the tumour).

3. The half-life of AVA6000 in circulation before excretion - i.e. the number of passes of the tumour and the percentage of dosed AVA6000 at each pass.

3 will be found in the PK data.
2 will be hopefully be found in any biopsies (supporting findings from the animal studies).
There is great variability possible with 1 and could be decided based on how long it takes for dead tumour cells to be shed, exposing fresh FAP-rich targets, or, if AVA6000 pervades the whole tumour, a single bolus dose.

RE: Synergy
22 Jan 2023 17:43

Well, permeabilty/penetration could be increased by smaller doses at more frequent intervals for instance - not that the two are correlated, just intervals that allow time for the dead tumour cells to disperse before hitting the tumour again.

Anyway, lots of possibilities now that the mode of action has been proven and who knows what Avacta and the SDMC have in mind, except that it will be

Whilst the whole paper is worth a read here are extracts from the Discussion section:

"The relatively poor penetration of doxorubicin is probably due to rapid uptake of the drug by perivascular cells. Doxorubicin binds avidly to the DNA within these cells, thus reducing the amount available for diffusion to distal cells. Our study provides a rigorous quantification of doxorubicin penetration length and extends the work of Lankelma et al. (9) to reinforce that chemotherapy with DNA-binding drugs, such as doxorubicin, is limited by poor penetration of tissue. In addition to quantifying gradients of doxorubicin, the methodology used here relates the distribution to multiple vessels (several hundred per image) and to regions of hypoxia. The identification of hypoxic tumor regions facilitates the recognition of viable cells that are not exposed to the drug after treatment.

"Some human tumors respond well to doxorubicin in spite of its relatively poor penetration. Among the tumors studied here, the 16C tumor was much more sensitive than the EMT6 and PC-3 tumors despite similar distributions of doxorubicin. Possible reasons for this include: (a) differences in intrinsic cell sensitivity to doxorubicin, (b) differences in the number and distribution of clonogenic cells that retain the capacity to regenerate the tumor after treatment, and (c) better distribution of active metabolites of doxorubicin, such as its major metabolite doxorubicinol. Better distribution of doxorubicinol seems unlikely to convey drug sensitivity because the metabolite is considerably less toxic to cells than the parent drug (14). Sensitive tumors might have a smaller proportion of stem cells that are distributed preferentially around blood vessels. Although not apparent among the three tumors studied here, differences in blood flow, concentration, and organization of blood vessels could also contribute to differences in drug sensitivity. Sensitive tumors could have a larger proportion of perfused vessels and/or smaller intercapillary distances and hence fewer cells lying beyond the diffusion range of the drug. Moreover, repeated treatments with doxorubicin might lead to the killing of successive populations of cells at increasing distance from blood vessels (analogous to peeling an onion); although this will depend on the relative kinetics of cell killing and of repopulation from surviving cells (15, 16)."

"In summary, the results presented here show that the distribution of doxorubicin in solid tumors is poor. The sensitivity of tumors to doxorubicin is likely to depend as much on drug distribution (and the spatial distribution of clonogenic cells within the tumor) as it is on intrinsic drug sensitivity. This important and neglected cause of clinical resistance to chemotherapy is likely to apply to other drugs, including monoclonal antibodies and some molecular targeted agents. Moreover, drug distribution is amenable to modification. ..."

I came across this just now. The full text is freely available online.

The Distribution of the Anticancer Drug Doxorubicin in Relation to Blood Vessels in Solid Tumors
https://aacrjournals.org/clincancerres/article/11/24/8782/188867/The-Distribution-of-the-Anticancer-Drug

"Abstract

"Purpose: Anticancer drugs gain access to solid tumors via the circulatory system and must penetrate the tissue to kill cancer cells. Here, we study the distribution of doxorubicin in relation to blood vessels and regions of hypoxia in solid tumors of mice.

"Experimental Design: The distribution of doxorubicin was quantified by immunofluorescence in relation to blood vessels (recognized by CD31) of murine 16C and EMT6 tumors and human prostate cancer PC-3 xenografts. Hypoxic regions were identified by injection of EF5.

"Results: The concentration of doxorubicin decreases exponentially with distance from tumor blood vessels, decreasing to half its perivascular concentration at a distance of about 40 to 50 µm, The mean distance from blood vessels to regions of hypoxia is 90 to 140 µm in these tumors. Many viable tumor cells are not exposed to detectable concentrations of drug following a single injection.

"Conclusions: Limited distribution of doxorubicin in solid tumors is an important and neglected cause of clinical resistance that is amenable to modification. The technique described here can be adapted to studying the distribution of other drugs within solid tumors and the effect of strategies to modify their distribution."

A, but that's because of my stage of life.
Would be B if I was younger.

I'm really worried now. So many speculative oil and mineral companies have collapsed. What does this mean for Avacta????? Surely a death spiral!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!1

There will only be a rerate when there's a clear path to revenue. The visionary will see that with excellent safety and tolerability data and very strong initial indications of efficacy (biopsies, tumour measurements, obvious reduced or lack of doxorubicin side-effects) and load up. The dullards will wait until the ship is sailing.

The 200mg/m² one? That would be 135mg/m² doxorubicin equivalent, so 3 cycles would have been possible.

I suggest that 3 data points are the absolute minimum for obtaining a meaningful graph.

At 280mg/m² AVA6000, 3 cycles would take the total administered doxorubicin to 567mg/m² which is higher than the top of the 450-550 doxorubicin CTLD range. So if there are to be dose escalations (plural), that doxorubicin CTLD limit would have to go.

Except that a DE to, say, 240mg/m², which is equivalent to 162mg/m² doxorubicin equivalent would only allow two cycles (from a starting point of no prior doxorubicin) to keep under the 450mg/m² CTLD, if indeed 450 is the limit, and they surely want to be going even higher if the intention is to find MTD - "higher dose cohortS" plural.
I just don't think it is possible/useful to escalate the dose within the constraint of doxorubicin's traditional CTLD. And, speaking personally, if I wanted to up the allowable CTLD of AVA6000-delivered doxorubicin I'd also want to increase the frequency of administration (shorten the cycle time) as the body doesn't need the 3 weeks to recover from doxorubicin-indiuced side-effects.
Such changes would need to go to MHRA, FDA and their respective ethics committees, and that takes time. If the starting gun for this was back in November/early December, then a decision is surely due soon (expected by Avacta by Science Day?) according to the FDA (at least) 30 day or 60 day or whatever it is time limit for responding.

I just put it there for people to read, and listen to if they want to check on the veracity of my transcription.

I don't give a flying fugg about the FUDders. They have no interest in Avacta or AVA6000 succeeding, only in their own greed. It's up to everyone whether they want to assign any value to anything such people write rather than doing their own research and having faith in their own judgement.

As for Science Day, it will be what it will be. Nothing said or done then will affect the results obtained so far.

.co.uk of course

https://www.**********.co.uk/articles/alastair-smith-of-avacta-successful-completion-of-fourth-dose-escalation-in-ava6000-phase-1-clinical-study-5e35ec7/

v o x m a r k e t s .com

@ 6:35

"The data are unequivocal. I'm delighted to say that doxorubicin IS [his emphasis] being released in the tumour tissue and at significant levels, therapeutically relevant levels. So, we know that from analysing tumour biopsies from six patients across several of the cohorts. We're seeing doxorubicin in ALL [his emphasis] of the tumour biopsies that we've taken, and it's clear that AVA6000 can deliver a therapeutically meaningful dose of doxorubicin into the tumour tissue whilst, when we measure in the bloodstream at exactly the same time, the concentration is very much lower, as we would hope."

That's unequivocal. Anyone who wants to dispute any of that should take it up with Alan personally as arguing here against what Alan said is just noise.

Well apparently a Science Day was an annual thing until covid., or so I've read here.

I don't know the format of previous ones and it doesn't really matter. For this one, Avacta have news to impart - otherwise they would have stuck with the original November tmeframe (itself delayed from September) - and are inviting KOLs in oncology to share their knowledge.

We've had no official notification of who the KOLs will be, and there's no reason why we should be notified. Maybe the invitees have been told, maybe they haven't; it doesn't matter either way.

There are similar schemes from other regulatory authorities. AVA6000 should be eligible for these as well.

MHRA's
Orphan medicinal products: https://www.gov.uk/guidance/orphan-medicinal-products-in-great-britain
and
ILAP: https://www.gov.uk/guidance/innovative-licensing-and-access-pathway

EMA's
Orphan designation: https://www.ema.europa.eu/en/human-regulatory/research-development/orphan-designation-research-development
and
PRIME: https://www.ema.europa.eu/en/human-regulatory/research-development/prime-priority-medicines