Member Info for CTSFO

Never a truer word:

“When the 'echo chamber' starts deleting posts with contrary views the board has no purpose at all.”

Censorship is the action of dictators.

The condition of the patients was explained in the initial RNS and the trial protocol listed with the MHRA / FDA.

If I had pancreatic cancer I’d take AVA6000. A lot of AVA6000. FAP secretion in pancreatic cancer:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9574192/

How is it FUD if it’s actively supporting the company?

Dosing every 2 weeks.

Nothing wrong with that! If I had Thorn’s investment strategy, I wouldn’t be sitting on the paper loss I have. I’d rather be buying in down here. Such is life. As long as it comes good for all of us.

GLA

An update on the Q2W trial wouldn’t go amiss either!

Q2W results will add to the dataset, and will be very important. It might well be the news we all want. But a P2 will still need to take place. Excellent Q2W results might make P2 easier to JV fund, or raise at a premium? It’s going to be expensive if Avacta plans to keep in house all the way to market. But worth it long term.

In the meantime, AACR will provide some information into the news vacuum we’ve had.

More clueless than guessing, I’m the first to admit it. I’m not an II. I don’t know what is happening behind closed doors. I don’t know how Al behaves with these people. I can see both sides of the argument here.

AACR will tell us more about the research: that I will understand.

GLA

That makes sense. So many unknowns at present. But let’s be honest, no one is going to invest £20,000,000+ if it’s simply going to go bits up. We know they’re getting cheap shares, but this type of investor is in for the long game. And not to see the sp plummeting.

The investment side of this I’m cr@p at understanding. The more I look deeper and deeper at the science, the happier I am to be invested.

Ice, Bella, they are good points. I should have also said that maybe what they’re seeing is so good they’re committed to going it alone?

Touk, last bit of mind numbing science…

Something else from C7, and it touches on the discussions you, Ice, and me have had about Q3W and Q2W. It’s about the rate limiting step. All this in the attached article.

Plain doxorubicin enters the cell by simple diffusion, down the concentration gradient, across the cell wall. Once in the cell it forms a proteosome-doxorubicin complex and gets carried into the nucleus. Doxorubicin affinity for DNA is higher than the proteosome so it binds with the DNA.

So concentration of doxorubicin:

Nucleus > cytoplasm > plasma. But we know not enough is carried in the blood (peak concentration and duration toxicity limited) to allow all of the tumour to take it up. Hence the drug level gradient seen in solid tumours. This is the rate limiting step normally.

With very high concentrations of AVA6000 in the more recent cohorts, will FAPalpha be able to cleave AVA6K fast enough to allow a ‘massive’ concentration gradient- through all cells in all of the tumour? Massive gradient leading to an overwhelming amount of drug in the cell?

Maybe allowing mitochondrial dysfunction triggering cell death as well as the DNA damage?

https://onlinelibrary.wiley.com/doi/full/10.1111/j.2042-7158.2012.01567.x#:~:text=This%20process%20occurs%20as%20doxorubicin,pore%20complexes%20into%20the%20nucleus.

Wyndrum, evening, sorry for delay.

Fair points and questions. The tone has changed. Has someone had a word in Al’s ear? Not sure who ‘polices’ RNSs and CEO comments where drug development is concerned. A formal reprimand from a regulatory body would be on public record. Have results not lived up to the expectations? Again don’t know, but we’ll find out in April.

I’m wondering if a potential big investor has backed out at the last minute, forcing this action? It’s the easiest explanation. If this is the case, then we’d want to know why?

It is what it is. Let’s wait for April and find out?

GLA

Afternoon Wyn. A possible answer: P1a is designed and powered to be a FIH / Safety trial only. Trying to extrapolate efficacy from this could land the company in hot water with drug safety regulators. They can present case studies as statements of fact, they simply can’t claim efficacy at this point.

The share price will go up when people understand the science, how it gets proven, and the enhanced therapeutic index of AVA6000 vs plain doxorubicin. I know it’s boring, but it’s what it is.

🤔 It’s actually not boring to us geeks who have to use therapeutics on a daily basis. Each to their own. Hope you make a damn good profit here.

GLA.

The importance of the Stroma with regard to cancer proliferation can’t be underestimated. One example in this paper. I wonder if a high enough TME concentration of doxorubicin will cause cell death of the stroma cells, as well as the cancer cells? All this supports AVA6000 as a delivery platform. Both peak TME concentration and sustained level of drug are very important here. This paper suggests the time between dosing is when the stroma is at play. Which makes sense.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10646478/

I agree. Low free doxorubicin in the plasma, and no MTD, proves the safety of the platform so far.

Ideally we’ll see supra normal delivery of doxorubicin into the TME and tumour cells. We need to avoid concentration gradients of doxorubicin within the cancer. High in the periphery, low in the centre. This has been shown in prostate and breast cancers.

https://aacrjournals.org/clincancerres/article/5/7/1703/287594/Doxorubicin-Gradients-in-Human-Breast-Cancer

The reason I hope the TME level remains high is that this might, very much a might, reduce the ability of cells to develop the MDR where doxorubicin is actively pumped out of the cancer cell.

GLA

Morning all. I agree that Q2W may well be the trigger point for BP interest. One of Avacta’s own presentation slides says they think Q2W is the optimal dosing regime.

What I’d like to see at AACR:

Safety: the same safety profile we’ve seen to date. Some side effects, but low grade. I’d be interested in any evidence of cardiotoxicity, have Avacta tested for myocyte damage using ultra high sensitivity Troponin assays? Has there been any evidence of cardiotoxicity in the early cohorts. Unfortunately, the cardiotoxicity can develop some time after the doxorubicin has been stopped. Not sure if a raise in troponin T during treatment is always a precursor of myocardial dysfunction later on. But the lower the plasma level of free doxorubicin, the lower the risk of heart damage. So also seeing the plasma free dox concentration against time would be useful.

Efficacy: P1a so not an efficacy trial… but… I’d like to know what the actual levels of doxorubicin was within the cytoplasm and nucleus of the cancer cells, and also within the TME - if at all possible. Real life results on effect of treatment on cancer size and how many patients are still alive. I think we’ll be focusing on the patient(s) with sarcoma.

If we look at just how many presentations are being given, it gives an idea of the range of companies BP can chose to become involved with. Obvs not all are Pharma, but it shows we’re not alone. Avacta needs to up its game in getting the message out there.

GLA

Why this matters… if the cohort data presented shows marked reduction in toxicity, especially myocardial, and we’re seeing a defined and quantified uptake of doxorubicin into the tumour cells / TME people will take more notice. It’s possible Q2W will be the sweet spot for AVA6000. It’s going to be very interesting if the patient with sarcoma is still alive.

GLA