Member Info for jive_turkey

@Nanomat and icecool: this is literally what happens at every financial update and AGM. News is not scheduled around these events. And they always offer the opportunity for investors (or potential investors) to ask questions. And yes, I'm sure that 90% or more of the questions are the same from one event to the next (3 years ago all questions were about updates to the LFT and today they will all be on updates of ava6k trial).

Of course, there may be news dropped in the meantime, but as we have seen every six months for many years now, the financial updates are not events scheduled around news, or even opportunities used by the company to provide meaningful updates.

Thanks gje, great post! I was struck by this line, talking about previous attempts to use FAP: ". Those drugs that underwent clinical trials had limited success. FAP-targeting immunotherapy has demonstrated a nonselective recognition of FAP-reactive T cells on pluripotent bone marrow stem cells. It led to lethal bone marrow hypocellularity, necrosis, and cachexia."

As I recall a quote from AS in the spring of 2022, when referring to the pre-clinical data of ava6k: "Other companies have tried, and failed, to achieve this level of specificity [in targeting FAP]." And we know from C1-C5 that ava6k has an excellent safety profile. It seems that have, indeed, cracked this problem.

@PL: my understanding is that the box to check relates to the number of patients. And that is the difference between p1b and p2.

@lda: no it doesn't. mtd has no relation to how p1b/p2 are planned.

@pl: yes, i think that there is something to this. they won't skip p1b, but p1b is effectively a p2. if the signal of efficacy is clear (and from everything we have seen so far, this seems very likely) in p1b, then there can be "limited approval" by the fda after p1b. this means that p2 is still required, but that sales can commence and patients can begin to benefit. if p2 doesn't show the kind of expected benefits foreseen, the approval can be rescinded. a recent example of 'limited approval' is lartruvo, which was approved after p2 and sales commenced. in this case, the drug failed p3 so the approval was rescinded.

the approval for ava6k would be for sts. but here is the bigger question for me. can it also be used off-licence with limited approval? imagine you are a doctor that treats a fapa rich tumour type (e.g., breast cancer) that often is treated with dox. wouldn't you prescribe ava6k in this case? if i had breast cancer (or ovarian or pancreatic) i would be pretty ****ed off if i wasn't given the chance to benefit (no cardiotoxicity, little-to-no side effects, etc).

if you want a big example of recent off-licence drug prescriptions, see ozempic. this is a glp-1 analogue used initially by diabetics. it has been shown to be an effective weight loss drug, but (at least in the uk and europe) it has not been approved for weight loss yet. however, it is prescribed off-license for weight loss, and the the amount they sell as a 'weight-loss' drug dwarfs the market for diabetics.

yes, this is definitely speculation, but with solid examples backing it up. sts is a rare cancer (and even then with a large possible market), but things get exponentially more exciting when considering other fapa rich tumours that respond well to dox.

@Neut: it's a good question, and one that has been debated on here a few times. The question is whether the lifetime/cumulative dose limit is based on the amount of dox injected (in this case, as part of ava6k) or whether it is measured in the blood (to take into account ava6k's targeted nature). I asked this of FMcL at the AGM and she confirmed that it was measured in the blood. So, due to the fact that ava6k is much more targeted than straight dox, it is not restricted by the same limit.

Comparing the amount of dox seen in the blood in C1-C4 (given to us on the SD slides) to the amount of dox in the blood when given straight dox (both at 24 hours after infusion - the latter can be found in papers in the literature) it seems that there is ~5 times less dox in the blood (for the same effective dose) for ava6k than for straight dox. So, to first order, the lifetime cumulative threshold of dox will be reached at ~2500 mg/m2 (or 3700 mg/m2 of ava6k). None of the patients dosed so far will be anywhere near that level...so not something we need to worry about for the forseeable.

Ah the peace of the green box....

That Touk and Wyndy both posted after a 3 hour lull in posts on the BB. It is clear that their job is to generate posts. They simply say something controversial, something that they know people will respond to. How tedious.

@Moneysponge: No, if the effect (i.e., death) happens after the infectious phase (like in case of the coronavirus) then there is little or no selection pressure to become less deadly.

In retrospect, yes, the window for LFTs was quite short, so every day mattered. However, that was not a given, and in fact argued against by most scientists and governments. But viral mutations are random and chaotic, so there was always a possibility of it becoming less deadly. And we got lucky that it did.

https://www.politifact.com/factchecks/2021/dec/08/facebook-posts/viruses-and-other-pathogens-can-evolve-become-more/

It is difficult to know sometimes if posters are being intentionally provacative or are simply misinformed/mis-remembering what happened during the LFT period.

@Ianbt: In 2020/2021 the UK was using 10s of millions of covid LFTs per month. And this was just the UK, the USA was much more and testing was hugely common around Europe and Asia. The potential market for a cheap and accurate test was in the 10s to 100s of millions per month. It took longer than expected to finish the test (I'll grant that), but it was ready in January 2021. However, due to delays in getting it verified (largely outside Avacta's hands), it wasn't approved for sale until June 2021. At that time, there was still a very significant LFT market although it was only approved for businesses (i.e., with a health care professional present). Again, due to delays in government processing, it wasn't approved for home self-test until Dec. 22nd, 2021. Even at that time, the market for LFTs was still quite significant.

Around November 2021, the Omicron variant became the dominant variant in Europe and the world. Humanity got very lucky as this variant was significantly less deadly but outcompeted all the other variants. This was by no means a given that this would happen, i.e., look at smallpox, HIV and any number of other viruses that have not gotten less deadly with time. It was at this time, due to the decreasing severity of infection, that testing took a massive dive. There is no way that Avacta could have predicted this. As we know, the LFT didn't do particularly well with Omicron (although from everything i've read most other LFTs also performed much less well with Omicron, they simply didn't advertise this fact), but that was largely irrelevant as the need for testing dropped massively at this time.

Hence, the estimates provided by the company and by many posters on this board were reasonable and accurate given the information that we had at the time. The delays imposed by the UK government meant a delay of ~12 months or more, which did significantly affect the number of tests that Avacta could sell. Luckily, for humanity, the need for mass testing evaporated in late 2021/early 2022. This was unlucky for Avacta and us SHs from a monetary point of view.

Posted this on twatter last week, comparing dox market to that of ava6k.

2.7x - the amount of dox per cycle of treatment (if they dosed at C6 levels)

3x - three times the dose allowed (Avacta have stated that one of the goals is 2-3 times the number of cycles)

2x - the patient population (people above 65 and others with e.g., heart conditions)

2-10x - the cost of ava6k vs. dox, i.e., on-patent drug vs. generic. Typical values in the field of 5-10x...2x would be an extreme lower limit.

Total: ava6k would have expected sales of 32 - 160x more than straight dox for STS alone. And while it may take a couple years to take over the entire market, I think it would actually be relatively quick. Look at the sales of Lartruvo to see how fast it can rise, even with questionable efficacy. So whether the dox STS market is $1 or 2 billion doesn't matter much.

Remember STS is a rare cancer. Now, start using ava6k on breast cancer, lung, ovarian, pancreatic, etc, and the above numbers are dwarfed. Of course Avacta would have to demonstrate superior efficacy and/or safety to move into those tumour types over their standard of care. But dox was used as a first line against many of these tumour types until recently, so we know it works there. Take away the worst of the side effects and it's not hard to see ava6k becoming the standard of care for many of these tumour types in the not-too-distant future.

The first steps on this path will hopefully come in the next weeks/months, as soon as some initial efficacy data are shown.

I predict C6 finishing and C7 starting this week or next at 380 mg/m2.

@LDA - do you actually think that they would put out an RNS saying "We think MTD might be close." No company would announce a guess, they will announce it when it is seen/measured.

For cash flow and future financing, they had the AGM in June. How often do you want an update? I guess what you really want to know is what kind of deals they hope to do in the future. Again, no company would announce this.

As for the dx integration, in what sense? What info do you want here? let's just say "good". Each company kept their management in place, so there isn't much to 'integrate'. If you want to know if any new affimer based products are coming out soon, the answer is no. We were told at the AGM that it takes ~3 years to bring a new product to market.

It's summer, July and August are typically low news months.

@Thompi - nothing is official for P1b yet, but yes Avacta have mentioned in slides (and at the AGM) that it is possible/likely that they will be changing the dosing cycle from every 3 weeks to every 1 or 2.

@MrPinchy - no. Either they find MTD in C6 or they move on to C7. At the end of C7, if they haven't found the MTD, they then have a choice to either continue dosing higher or define BED.

@Purple1 - no, I don't think so. Finding the MTD (or as close to it as possible) is near essential in this study. This is what is going to define the range in all further studies, i.e., studies using ava6k for other cancer types. It is possible that e.g., STS will respond to a lower dose of ava6k than tougher types like pancreatic. So in order to get the best chance of success for all future studies using ava6k it is worth putting in the time and effort now to get to MTD. This is also a number strongly recommended to get by the FDA for regulatory reasons.

@B2HS2L - yes, indeed I used 'blood' and 'plasma' interchangeably for simplicity, but of course all the measurements were done accurately.

@BV - I simply used a linear regression on the 7 data points in the SD slides. You are right though, there is a lot of scatter, so if I wouldn't include the first 2 points, it is a steeper relation so the conclusion would be that in C6 there would be about as much dox in the blood than in the 50mg/m2 case.

When we first got the Science Day slides, I posted on the amount of dox seen in the blood plasma and within the biopsies. As has been noted by myself and others, what we really want to see is the concentration of dox in the tumour when dosed with 75 mg/m2 of naked dox, so that we can compare directly with how much is seen in the different cohorts (and I would love for the company to update the SD slides to include all the info from C5 and eventually C6). I, for one, am fairly convinced that the concentration of dox in the tumours from ava6k will be far above that seen in naked dox...but of course we all would love to see the data (which will come in P1b).

But we can also look at the plasma. There have been a number of papers that have looked at the level of dox in the blood at 24 hours, which we can compare C1-C4 results against. Here is one example: Fig. 9.5 in "Cancer Clinical Pharmacology" edited by Schellens, McLeod, and Newell, 2005 (it's available on google books). For a 50 mg/m2 dose at 24 hours, the concentration in the plasma is ~25 ng/ml. C1 in the ava6k trial received an equivalent dox dose of 54 mg/m2, so effectively the same, and they had dox plasma concentrations of 4.9 ng/ml. So there is 5 times less dox in the blood with ava6k than for naked dox at the equivalent dose.

If we extrapolate using the 7 patients with dox measurements shown in the SD slides (from C1-C4), for C6 patients (which has an equivalent dox dose of 208 mg/m2) we would expect a dox blood concentration of ~16 ng/ml. This is still ***below*** that seen for naked dox at the low dose of 50 mg/m2 (which has ~25 ng/ml). Hence, even at the high dose used for C6, the amount of dox in the blood (at least at 24 hours after infusion) is still well below that of a low dose of naked dox.

The occurence of side effects is a complex issue, and it depends on Cmax (i.e., the peak amount of dox in the system) and AUC (the total dox experienced in the system), although it seems more related to AUC. And we only have 1 time point per patient/dose, so we don't have the full dataset. But, at least to first order, this suggests that patients in C6 will have with less dox in their system than patients on a low dose of naked dox. Hence, I would expect their side effects to still be relatively low (compared to naked dox).

Based on this, I expect a C7. But I am also hoping for some statements regarding the trial so far, like we got in the last RNS, that multiple patients are still on the trial due to a lack of progression of their disease.

Hi BV, at the AGM we were told that many on the BOD did have considerable amounts of shares that weren't "visible" to the community, which I took to mean that they were in their spouses/family's names. This made sense to me, why would they buy shares in their own names? Once they did that, effectively, that is money/funds that they can't reasonably touch. I.e., it is just stuck there. Just look at the crap AS took when he sold some shares to buy the house. So once they buy in their own names that money is locked away. If they buy in their spouses names, they are free to buy and sell as they wish.

Hi BV. I wasn't too clear on this either, had to go to Point's Canseek website. Effectively, they have a treatment that is made up of a radionuclide (the thing that is releasing the radiotherapy) and another molecule. That other molecule is included as it bonds to receptors on the surfaces of cells. Together, the radionuclide and other molecule, make up the radiopharmaceutical. Normally, the radiopharmaceutical goes around the body, and bonds to receptors on cells, so it may bond with a tumour cell, or just a normal cell. Hence, the off target delivery.

Their Canseek technology (i.e, Precision) does exactly what it does for ava6k. It makes it so that the treatment (in this case the radiopharmaceutical) is inert within the body, so it doesn't bond with any cell receptors. However, when it encounters FAPa, the cleaving happens, leaving the standard radiopharmaceutical and the leaving molecule. The radiopharmaceutical is then free to bond with cell receptors again, and since this cleavage happens predominantly in the TME, it is most likely to bond with a receptor of a tumour cell.

Presumably, they have to have the cell receptor bonding molecule or else the radionuclide would be cleared from the body too rapidly. Once it is attached to the cell receptor however, it can decay and emit a radionuclide whenever it feels like it (as long as that bond lasts longer than a few half-lifes of the isotope).

@ipadtrader, that isn't true. Informal bids do not need to be put to shareholders. How it normally works, or so I've gathered (see the recent buyout of twitter as an example) is that the bid remains 'informal', until the management of the company to be bought agree to it, so that when it is announced to the shareholders it can be stated that the management recommend accepting the buyout.