focusIR May 2024 Investor Webinar: Blue Whale, Kavango, Taseko Mines & CQS Natural Resources. Catch up with the webinar here.
Morning all.
“ Two DLTs were observed of grade 2 cardiac failure (120 mg/m2; LVEF decrease 61 to 39%) and grade 4 neutropenia/ thrombocytopenia (200 mg/m2.”
Not the best constructed sentence.
1 patient (only one thankfully) has had a cardiotoxic response. This occurred in the second cohort, announced to start back in Feb 2022.
There’s going to be interest in the time between dose and the cardiotoxicity occurring. It’s well known that the cardiac damage can be delayed with doxorubicin. Hopefully the ongoing surveillance of the participants will show this is a very rare occurrence.
OR. If not very rare, it is balanced by far greater tumour cytotoxicity being associated with the significantly higher free doxorubicin in the TME.
(LVEF Left Ventricular Ejection Fraction. The relationship between the end diastolic volume (full heart) before ventricular contraction, to the end systolic volume (‘empty heart’) at the end of a normal contraction.
The paper:
https://www.sciencedirect.com/science/article/abs/pii/S0009898119320674
Evening. Reference paper to follow.
“ Remarkably, some types of chemotherapy-induced cell death exceed the pure antineoplastic effect. Anthracyclines, a widely used class of chemotherapeutic agents, are known to induce an immunogenic cell death (ICD). Anthracycline-treated tumor cells release immunogenic damage associated molecular patterns (DAMPs) such as HMGB1 or calreticulin which stimulate antigen presenting cells and promote a T-cell response against tumor cells [5].”
AVA6000 will only work in FAPalpha rich TME / tumours. We know this. Could tumour cell death biomarkers be used as a way of assessing / proving tumour death is taking place? Some trials are taking place on radiotherapy of cervical cancer and seeing if there is an association with long term survival. I’m wondering if we’ll see something similar being trialed with the AVA drug family?
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/
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.
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.