Member Info for jive_turkey

@LL - yes, except at the science day deck we were not given the equivalent results (biopsies and concentrations) for straight dox. What the numbers below the table show was the expected IC50 rate for dox, but this was in a petri dish, not in a human. And while one should expect them to be close, biology is such that surprises are common.

But even with this, I realise that concentration of dox in the tumour for ava6k and straight dox are not directly comparable at a single time point (24 hours after infusion in this case) due to the different PK properties between ava6k and straight dox. Dox from ava6k might be lower in the tumour than straight dox at a given time point, but if it last for longer the cumulative amount of dox in the tumour could be much higher.

But all that uncertainty is behind us now, the risk is gone, efficacy has been demonstrated and as has been noted (but under-appreciated in my view) is that even for very successful drugs efficacy isn't seen in P1a (due to the patient pool). So that fact that we see it now (so much so that the P1b has been dropped), so clearly, means that ava6k is looking very special indeed.

FWIW, I think that there was still significant risk that ava6k wasn't "working" during C1-C4, even maybe including C5. Yes, the biopsies that were taken showed significant dox levels in the tumours, and this was a big signal that it was working. But there was still a chance that due to the different PK properties of ava6k vs. straight dox, that the concentrations reached would not be high enough to really help destroy the tumour. For example, ava6k should dampen the big early spike of dox in the blood when given as straight dox. Ok great, but if ava6k was cleaved at too low a rate in the tumours, it is possible that there wouldn't be enough dox around to kill the tumour. As AS has stated, until a few months ago, there weren't any clear efficacy signals in the patients. That wasn't entirely unexpected (given the patient pool that comprises P1a studies), but it meant that it was still a risk.

But we now have clear efficacy signals in multiple patients. So this risk has been removed. AS and FMcL have recently stated that there is now little risk involved for ava6k and that everyone in the know thinks that ava6k will work and be approved. The only risk mentioned is one that they are on top of, namely making sure that the P2 study is well designed (i.e., sub-types used).

For common tumour types (e.g., breast, lung, ovarian, etc) there are many drugs that have been approved, so there is is certainly competition between the different makers to get their drugs used more often. But that hasn't stopped many of these drugs from becoming blockbusters (>>$1B in sales). So competition is unlikely to be a significant hurdle either, even before one considers the special position that ava6k finds itself in, i.e., an effective drug with drastically reduced side effects (and no cardiotox!).

That's a good point PL. My hope, however, is that these new retail investors won't be traders for the most part, but rather normal Brits who are investing for the future. Traders seem to love AIM, while investors seem to shun it, by and large.

I think that there will be three causes of SP after data release. The first, like others have said, is if we get a large fund or a large pharma to take a large stake in the company. And making the data public (assuming it is as good as it has been implied) increases the likelihood of this enormously. Secondly, the published data make the possibility of a license deal much more likely. It is these two that will see the SP much closer to the deserved level.

The third is if the data release contains info that can be picked up by the main stream media. "Terminal cancer case gets miracle cure"...that kind of headline. This would introduce Avacta to the public at large, and will double or triple the retail investment base overnight. But this of course requires making the front pages of the newspapers and onto the headline stories of BBC news.

The latter, by itself, would probably put at us ATHs (300p+), but the former (first two) is where the true value lies (1000p+).

Excellent point CTSFO. I asked ChatGPT "Are case studies usually given with Phase 1 oncology results?" and this was the response:

Case studies are not typically presented alongside Phase 1 oncology clinical trial results. Phase 1 clinical trials are primarily focused on assessing the safety, tolerability, and dosage of a new drug or treatment in a small group of patients. These trials are designed to determine the maximum tolerated dose (MTD) and evaluate the drug's side effects.

Case studies, on the other hand, are typically detailed examinations of individual patients or a small number of patients, often conducted in a clinical setting. They provide in-depth information about the medical history, treatment, and outcomes of specific patients. Case studies can be valuable for illustrating unusual or unique clinical scenarios and are often used for educational or research purposes.

Phase 1 clinical trial results are generally reported as aggregate data, summarizing safety, dosage, and early efficacy data for the entire study population. These reports are important for regulatory and scientific purposes and provide the foundation for advancing to Phase 2 and 3 trials.

As clinical trials progress to later phases (Phase 2 and Phase 3), more extensive data on the efficacy of the treatment is collected, and case studies may be included in the discussion of these later-phase results to provide additional context or insights into individual patient responses. However, they are not a standard component of Phase 1 trial reporting.

@Timster - Good point about inclusion of C7. Avacta are collating and QCing all the data for C1-C6 (a process we are told is non-trivial and very time consuming) and the inclusion of C7 data may complicate matters. On the other hand, one could image the inclusion of C7 data that does not require detailed QCing, i.e., side-effect profile. And if we want to be very optimistic one could imagine (due to the higher dose level than C5/C6) that a patient or two might be experiencing significant tumour reduction in C7 who could make excellent case studies.

@CTSFO - I fully agree. Avacta are really talking up the P1a results from all angles, so definitely not your standard results.

@RMFatGB - nope. This morning it is at $1.99 which is £1.65. Compared to the £1.36 price in the UK (before the markets opened).

It's also at 17% above the UK price.

@BV - good point. Looking quickly at the literature, it doesn't seem that drugs are only approved for specific sub-types of soft tissue sarcomas. So it may be a case of selecting the sub-types where the best signal is expected in order to get approval and then use it for other sarcomas.

Because we were told that it is a relatively simple application to the fda, and that they expected to start the bi-weekly dosing concurrently with the completion of c7.

@Robin - I expect Avacta to issue an RNS when the FDA decision comes through.

I believe that the fastest cohort so far completed in 60 days. Based on that, the earliest C7 could be expected to finish would be the week of Nov. 20th. Before that I would expect news on the FDA decision on the bi-weekly dosing.

200 mg/m2 (135 dox equivalent)

Prion, please go this this webpage, and insert the URL you are trying to paste here. Then paste the new URL that it gives you here.

https://tinyurl.com/app

@Timster - correct, there are a surprisingly few number of papers with dox measurements in biopsies in the literature, despite being such a commonly used treatment. There are a few that I've found that take biopsies after ~1 hour, but the dox levels change significantly over time. I've found a couple papers with models of the amount of dox expected to be found in tumour and other tissues as a function of time, but none with real data in it. From the models, ava6k appears to be doing well, but again that is only at a specific time point, and not the integral over time (area under the curve - which is the important measurement).

Anyway, I think that the crucial observations so far is that multiple patients have had their tumour progression halted (i.e., remain on ava6k) and at least one has seen dramatic tumour reduction. Earlier in the trial AS made a big effort to temper our hopes up, i.e., that efficacy would not be seen in P1a due to the patient population (end of life patients after multiple lines of treatment). Yet here we are, P1a with clear signs of efficacy. In Cohorts 5 and 6, 13 patients were dosed, and I assume all/most were STS patients. Add another ~5 in Cohort 7, and we're looking at >15 STS patients dosed (minimum) in these later cohorts (high dose levels). Should see additional patients with 'dramatic reduction' in tumour volume, hopefully with some details released with the P1a readout.

Good questions BV. Unfortunately, I have seen any papers with those comparisons, in fact I don't think I have ever come across a paper (on dogs, mice or humans) where the dox levels in-vivo and in-vitro in terms of IC50 were compared. I'll keep an eye out for that, good point.

@RMFATGB & @Rambo23 - yes, we know that dox is getting in the tumour, proving the mechanism of action. We've also seen estimates of how effective these levels might be (i.e., IC50). However, there is a tiny risk here, as those numbers come from in-vitro experiments, not in-vivo (i.e., in a petri dish instead of in a human). And that's ok, the data just don't exist at the moment to do the comparison in humans. They planned to do the comparison in P1B (before it was changed, i'm not sure if it is still planned) of dox in biopsies when using ava6k and straight dox, so a direct comparison. Ideally, we would simply see that there is X times more dox in the tumour when using ava6k over straight dox. But it may not be as simple as this, as this would only be at a single time point. Due to the very different PK profiles of straight dox and ava6k (half-life and elimination time) a single time point may not teach us much. What we need is the integral of how much dox is in the tumour over time, i.e. the area under the curve (AUC).

This is exactly what they showed in the mice models, it was in the AUC where there was 18x more dox in the tumour than in the heart.

@DTW - I agree entirely. These are only 'risks' in a very inclusive sense, indeed the real question now is on the level of improvement. I just wanted to respond to the rubbish about 'risk' that FUDders keep brining up here and on twitter.

@Ticino - dox only kills cells that are currently reproducing (as it gums up the DNA replication). Tumour cells have a much higher reproductive rate than typical cells which is why it typically has more effect on the tumour rather than on healthy tissue. It's a very powerful drug although it is not 'tumour agnostic'.

Agreed DTW. In my view, there is only 1 risk remaining, because there is only one bit of info that we are missing. We don't know how much dox is in the tumour when using ava6k vs. straight dox (not just at a single point in time, but integrated over time) as well as what is the ratio in the blood.

Now, that said, while we don't have the actual numbers, there are good reasons to think that things are good to great with ava6k. They are 1) the pre-clinical results in animals, 2) the "therapeutically relevant" amount of dox in the biopsies of the tumours, 3) the fact that many patients remain on ava6k, meaning that their tumours have not progressed, 4) at least one STS patient has seen a dramatic decrease in tumour size as well as strong evidence of effectiveness in other patients (last RNS).

So we know it is safe, we know that the mechanism of action is working (cleavage preferentially in the TME), and we know that some patients are seeing beneficial response. Hence, the risk of not enough dox being released in the tumour is very low.

Thanks BV. Yes, there are definitely other options (like the one you suggested) as well. I should have prefaced my post that it was based on the statement (and slide) at the AGM that "The Precision Pipeline is now entering the commercialisation phase". I should have also mentioned that at the AGM, AS (in the presentation) emphasised the likelihood of point 7 in "the near term".