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Ah the sweet dulset tones of sausage
Dear Ophidian,
I did not claim there to be specific risiks, those
claims were raised in posts, you are - understandably - not able to see.
It’s what NDN does best. Repetitive & mind numbing.
Ndn is pure poison. Most will say ignore, but spooking people can’t be ignored.
Can't be arsed to paste question 22 in AGAIN but see above. Ndn once again trying to sow doubt....
First in human trial , very sick patients involved taken years to get to this stage. Selection criteria very thorough. Primary & Secondary outcomes detail explained .
A Study Evaluating the Safety, Pharmacokinetics and Early Efficacy of AVA6000 in Solid Tumours
"Brief Summary:
This open-label, First-into-Human (FIH) study will evaluate the safety, tolerability, pharmacokinetics (PK) and early efficacy of AVA6000, a FAP-activated pro-drug of doxorubicin, in patients with locally advanced and/or metastatic solid tumours. In Phase Ia, using a 3+3 design, escalating doses of AVA6000 will be administered to patients with a range of solid tumour types to determine the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D). In Phase 1b, the selected RP2D dose will be assessed in one to three tumour types."
read://https_clinicaltrials.gov/?url=https%3A%2F%2Fclinicaltrials.gov%2Fct2%2Fshow%2FNCT04969835%23contacts
https://clinicaltrials.gov/ct2/show/record/NCT04969835?view=record
@Alcibiades - I haven't read the whole of this somewhat rambling thread punctuated as it is by green boxes but to try and bring a little clarity:
Every clinical trial carries risks but if there were "specific" risks as you suggest then those would have been mitigated by additional preclinical work. Furthermore, the study is NOT trying to elucidate unexpected risks - utter nonsense. This is initially a dose ranging study which builds up the dosage to find the maximum tolerated dose - IF there is an issue or adverse event then ALL dosing would stop until it was explained and understood.
Once the MTD has been established - the second phase of this study will go ahead and that seeks to establish initially efficacy against a range of Tumour types.
This is not a Clinical Trial with a high degree of risk. Firstly it is an established Drug in Doxorubicin and secondly the modes of action are well understood from animal models. Contrary to what some nefarious types might wish to persuade you - Chemistry is not magic and FAP is FAP whether it's in a mouse, a person or a petri dish or test tube it is not reasonable or sensible to suggest that there will be any difference in behaviour in Humans versus the animal models.
Ophidian
To repeat myself: What evidence is there for any specific risk?
As far as I know none. The upcoming clinical trials will help to elucidate the presence of unexpected risks, but so far there is no specific risk to be expected. Otherwise they would be addressed in form of specific secondary endpoints in the study design. Unless we will find them there, the study designers and the approving authorities did not consider them to be expected.
Of course there is no guarantee for nothing in the medical field, but so far no specific risks endangering the clinical success have surfaced.
Again, here is the answer to your concerns:
Q22: AVA6000 - Are there significant amounts of FAP associated with Circulating Tumour Cells capable of causing the release of the chemotherapy away from the tumour?
Circulating tumour cells are very rare; there is approximately one circulating tumour cell for every million blood cells. The number of FAP positive circulating tumour cells is in the region of 26–49 per ml of blood. It is therefore unlikely that FAP associated with circulating tumour cells contribute significantly to cleavage of AVA6000 in the blood.
Relative to expression in most normal tissues, FAP is overexpressed on the cell membrane of stromal fibroblasts in many epithelial tumours and in soft tissue sarcomas. Thus, the preCISION platform provides a means to target the activation of a chemotherapy, such as doxorubicin in the case of AVA6000, to the tumour bed while reducing exposure of normal tissues.
(https://www.nature.com/articles/s41698-017-0028-8#Sec2)
Your abuses aside, there is neither evidence nor a rationale to assume FAP upregulated in tumour patients outside of the tumour microenvironment.
As to why Big Pharma usually doesn't acquire preclinical platforms is the fact it doesn't make sense for them to shoulder all the risks: if they wanted to, they could do such research in-house. On the other hand over the life cycle of a pharmaceutical IP some billions to acquire don't matter in the big picture. It's simple risk management to pay some billions for a safe profit of more billions in future sales, rather than risk hundreds of millions on an uncertain future.
The tricky points will emerge later on:
How much dose escalation is possible and is even wanted?
If you kill off tumour cells too fast you will convey into medical oncology all the problems haematologists struggle with in tumour-lysis-syndrome usually encountered in the treatment of leukemias and lymphomas (which respond often tremendously well to current therapeutic regimes) like clotting the kidneys with tumour debris and so on.
On the other hand of course the tumour and it's micro-environment will attempt to adapt to this therapy and clones scarecly or not at all expressing FAP in their environment will thrive. So maybe a special course alternating FAP-targeting and conventional chemo-therapy is needed to avert tumour-evasion.
Then there are cases known, in which tumour-entities are known to appear in different kind, either expressing FAP or not, for example this was shown for a common highly malign brain tumour called Glioblastoma multiforme. So there is the need to identify biomarkers predicting which patient harbours a tumour susceptible to this specific therapy (and most of them are as we already know).
It is a long way before this therapy can be routinely administered, but if the results of the animal study only somewhat translate into the clinical situation, medical oncology will see the next revolution after the introduction of checkpoint-inhibitors and chimeric-T-cell-therapies. This has the potential to be humungous in relevance for patients and in terms of revenue.
Well on serious wound healing and ongoing inflammations, especially those of infectious origin, those are a contra-indication to the start of any chemo-therapy anyhow.
As I said, at the moment there is no obvious or foreseeable flaw in the concept targeting FAP. It has been in the focus for quite some time now and the failure in translation as of now lies in the technicalities of proper targeting. Avacta seems to have overcome those hurdles as proven in their rodent study. Chances are very high this will translate exactly into man, and one can rest assured, all obvious points of contention regarding safety will have been thoroughly scrutinised by the regulating authorities. No patient will be dosed with something, a prolific reader and writer on an internet bulletin board can raise serious concerns about.
id like to know more about leakage from cancer cells post clevage but i guess thats what phase I is about
Quite the opposite actually. I should start blocking people…
I blocked ndn71 months ago
And I’m thick and unintelligent
Don’t reply to Ndn. He is properly weird. In the extreme.
Convinced he’s not invested here but likes the interaction on this board. Can you think of another investor that would find every excuse not to support the company? And by support, I don’t mean ramp.
It’s been said on more than one occasion - he’d make for one seriously long study. Give him 10 mins and he’ll be banging on about needing an increased validation study.
Ndn even if the precision and by association TMAC did not get over the line due to issues with Fap, then there is always the potential of Affimers and the freedom to operate without treading on an antibodies IP.
Think Keytruda roughly $15billion 2020 sales.
@Ndn71
The expression of FAP in adult human tissues is virtually absent, see
Pleshkan VV, Alekseenko IV, Tyulkina DV, et al. Fibroblast activa- tion protein (FAP) as a possible target of an antitumor strategy. Mol Genet Microbiol Virol. 2016;31(3):125–134.
As a highly conserved mammalian signalling pathway the preceding animal studies should hold true, unless a hitherto unknown effect comes into play. Hence the further clinical studies. As of now, there is no reason to suppose a significant expression of FAP in healthy adult human tissues.
Hard to overstate how exciting the results of this trial could be.
Q22: AVA6000 - Are there significant amounts of FAP associated with Circulating Tumour Cells capable of causing the release of the chemotherapy away from the tumour?
Circulating tumour cells are very rare; there is approximately one circulating tumour cell for every million blood cells. The number of FAP positive circulating tumour cells is in the region of 26–49 per ml of blood. It is therefore unlikely that FAP associated with circulating tumour cells contribute significantly to cleavage of AVA6000 in the blood.
Relative to expression in most normal tissues, FAP is overexpressed on the cell membrane of stromal fibroblasts in many epithelial tumours and in soft tissue sarcomas. Thus, the preCISION platform provides a means to target the activation of a chemotherapy, such as doxorubicin in the case of AVA6000, to the tumour bed while reducing exposure of normal tissues.
(https://www.nature.com/articles/s41698-017-0028-8#Sec2)
Regarding the pro chemo market, it really could be this big. Once a pro form of a chemo drug is licenced it immediately displaces the existing molecule pretty much completely. And simultaneously grows the market. Most of these drugs are off patent so there is lots of room for totally justifiable price increases based on significant patient benefit.
Its going to be difficult for Avacta to remain independent if there are good AVA6000 results. Not sure exactly where the proof point lies, certainly before the current trial completes in 2023, but critically its not theraputic results but simple pharmaco kinetics that will set the fire burning. If they can show that the behaviour in humans more or less matches that in mice, even in a small population its game on. Key is 10 times chemo in tumor, managable damage to tissue in the immediate vicinity, less chemo in vital organs, everything nasty expelled from the body in timely fashion. This would in itself be a huge step forward in everyday moderate cost cancer treatment. Because the linker technology is applicable, in a replicable way, with a whole lot of chemo molecules the development will be way beyond Avacta's capacity (think running 15 or 20 parallel development streams), and there will be pressure to get these up and running as soon as can be done. Maybe they could out licence the linker molecule by molecule, but this alone would generate such a head of stem that one of the big boys would want it all. Coz if this works it is potentially a $100 billion per year market to go at, if you can get your heads around that. That is titanic by any standards. Protecting the company for as long as possible is the name of the game, I hope they are getting advice from the city's most evil and ruthless bastards. Step one is getting the share price up by an order of magnitude. AS knows this I'm sure.
I think prof waffle likes to feel clever by working with the tech. Has a high opinion of it which is great but seems to have a blind spot about where money comes from.
He doesn’t see that interested in the business side, appears out of his depth. Sure we have some Nibe research agreements but nothing that generates meaningful revenue.
If the strategy is just to prove tech and keep fingers crossed that it’s recognized by a party with a big wallet then be nice to have that stated. Prof waffle said in an interview over a year ago that companies like Awacta don’t stay independent.
The covid test could have brought big revenues in. It could still make a difference but requires a market orientated helmsman/woman.
Worse case is 40 m the bank takes the company long way down the road of “hej look at this, make me an offer”. That’s what I’m holding on for and cash will last a good while.
Would prefer a therapy player rather than diagnostics. Have the feeling it’s worth more at TO buy is that right ?
Rorkes, can we at least dream? Of course you're right 2.4b£ is far closer to reality and from where we've been these last 3 weeks, it would be a dream. But I know from your many posts you are well aware of Avacta's IP added value. So if it can stay independent a while longer maybe we have genuine chances beyond 2.4b£. All my eggs are in this basket so yes I'm biased, but the more I read the well researched posts like yours and Piorot and many others, I just add a little more confidence despite the adverse political environment that frustrates us.
GLA.
Just spoke to sujood timster he said tomorrow will be MASSIVE