Member Info for jive_turkey

As discussed yesterday, we've been told by AS and others that understanding the efficacy of ava6k is not a primary goal of P1a, which is largely because not all tumors respond to dox. Ok fair enough, we can't expect an overall response rate (ORR) because the sample size is too low and we wouldn't have the comparison to standard dox (because it isn't typically used for that type). But could we expect a 'miracle case', i.e., something that the main stream media could pick up on? Something like "stage 4" cancer patient sees full recovery or maybe just "drastically reduced tumor size".

In the SD slide 81, we are given the cancer types of the patients involved in P1a up until then. We see that colorectal cancer (CRC) made up 11 out of 19 of the patients (~58%) and pancreatic cancer made up 5 out of 19 (26%). These are not the most common cancer type in the UK (C1-C4 patients were all in the UK), in fact they are 4th and 10th, respectively. In the list of cancer types to be included in P1a (clinical trials website); breast, prostate and lung are included, which are the 1st, 2nd and 3rd most common in the UK, respectively. So these would be expected to dominate the patient cancer types.

While there could be differences in the number of patients becoming terminal in each cancer type (i.e., available for a P1a study), the extreme difference between the number of CRC and pancreatic cancer patients in the P1a study, relative to the cancer rates in the population at large, argue strongly that the patients are not being selected randomly...or at least not fully randomly.

Pancreatic cancer had been highlighted by AS previously in presentations as a possible target, due to its high mortality rate (and high FAPa levels). If ava6k could be used to treat this, it would make a big splash.

CRC is not typically treated with doxorubicin. Hence, the comment by Avacta that the cancer types might not respond to ava6k. It is high in FAPa however, so a decent target to check the mechanism of action of precision.

But here's the catch, CRC *is* the tumor type that they used in some of the mouse models, specifically the one that culminated in the picture of the liver with and without ava6k treatment (i.e., where ava6k effectively eliminated the tumors in the liver). Hence, it is not too far of a stretch, I reckon, to conclude that some of the P1a patients with CRC may have displayed a significant reduction in tumor size due to ava6k.

After no 'miracle stories' were presented with the C1-C4 results were announced, i tempered my hopes of such success in P1a and instead looked to P1b. However, given that (human derived PDX) CRC tumors have already been shown to be treatable with ava6k, there is reason to be optimistic that we may hear about such cases when we get the full P1a results. If that's the case, this will be the inflection point in the SP we've all been waiting for.

@Neut, yes one way to look at the final buy out price is relative to the final Mcap, and calculate a "premium". But I haven't seen any evidence that this is how the negotiations work. Instead, there is an estimate of how much a treatment would be worth per year, within a given timeframe (say ~5 or 6 years) and factor in the chance of success.

In a functioning market (e.g., NASDAQ) the stock price already reflects much of these considerations, so the final buy out price is typically only 'a bit' higher, i.e. the 50-100% premium. But in our case, little or none of this has been priced in for whatever reason (in my opinion due to AIM...see article by AS and recent companies leaving), meaning our buyout price is unlikely to be strongly linked to the current Mcap.

The patients have been heavily pre-treated with dox or other therapies, which minimises the impact of further dox (ava6k). Additionally, some cancers (eg STS) respond very well to dox, while others don’t, and the patients aren’t chosen with respect to cancer type.

I agree with Timster. Highly unlikely in P1a. Definitely possible in P1b.

@RD, I'm not sure what your issue is here. Yes, many of us have been aware for quite a while that there is a multiplicative factor for ava6k due to the focus within the tumor. As I've written previously (as well others) the factor appears to be 3-4 for mice and indications are similar values for humans.

This only serves to strengthen my point. Considering a 1-1 comparison with straight dox (i.e., only correcting for the molecular weight difference) is the default comparison. This additional multiplicative factor only serves to increase the efficacy. At the C2, C3 and C4 dosing levels, the amount of dox seen in the tumor biopsies was already well above the threshold to activate the Free radical formation channel as well as the Topoisomerase Inhibition channel. So the factor of a few variation in dox level from patient to patient will not drop many patients below these thresholds.

If you are commenting that fitting a polynomial is somehow complicated, deep or magical analysis, I guess you're not coming from a science background. This is really a basic and standard thing to do when analysing data.

On to P1b! (sorry last line was cut off)

Pharmtechbio posted an excellent link that showed the overall response rate (ORR) vs. the dosing level of doxorubicin. ORR is the rate (percentage) of patients where their tumors significantly shrink by a specific treatment (chemo in this case). For naked dox, the authors found ORRs of 0%, 11%, 20%, and 37% for dosing levels of 25, 50, 60 and 75mg/m2, respectively. Remember that 75mg/m2 is the maximum tolerated dose of naked dox. The key take aways of this are 1) higher dox levels result in better ORRs and 2) it is clear that higher dose levels would likely be better, but they can't be used due to the associated toxicity of the drug in the body.

Ophidian fit a simple polynomial to the data to extrapolate to higher doses, and at a naked dox level of 135mg/m2 (i.e., the dose level used in cohort 4) the expected ORR is >95%. Of course this is just an extrapolation, but it highlights the potential power of ava6k (and note of course, that Cohort 5 is at even higher dose levels - 168 mg/m2 of naked dox).

Another take away from the above is that the ORR is actually quite low with standard dox (at the max 75mg/m2 level), only 37%. I've been wondering why there such a variety of patient response, many have positive results, while most don't have any significant response.

A partial answer to this, can be seen in slide 84 of the SD presentation. Take a look at the results for Cohort 3 as an example. At the same dose level (108 mg/m2) there is a factor of 3 difference between the concentration of dox found in the blood in the different patients and a factor of 3 also in the concentration of dox in the tumors. This is similar to what I've found in papers on the dox levels in the blood between patients. The take away is that differences in the biology of patients (maybe it is liver or kidney function, etc) results in a factor of ~3 (or a few) variations in the level of dox in their blood and tumor.

Dox mainly works through the 2nd and 3rd mechanisms in the table of slide 84 (i.e., Free radical formation and Topoisomerase Inhibition). If one then looks at the bottom table on slide 84, we see that for dox to work we need to get to 100-400 nM (this is similar to that found through the Chat GPT response). If we take the rates observed for the 1 patient (2 biopsies) in Cohort 1 as a rough estimate of what would be expected through the standard dose of naked dox (yes, it is lower, but we believe ava6k results in more dox in the tumor) we see that they would have only activated one route of dox - i.e., Free radical formation. Other patients may have gotten over 400nM....it's biology dependent.

The limited amount of dox that is allowed to be given, and the factor of a few variation in dox levels in the body, mean that dox won't be effective for many patients. The higher allowed doses Ava6k mean that even with patient to patient variations of a few, the vast majority should be in the range of dox concentrations to be effective. On to P

HI RD, I believe that AS has made this point multiple times, that naked dox diffuses throughout all body tissues, while ava6k focusses on just a tiny volume, leading to higher doses in the tumor and lower systemic values.

As for your second point, it's possible but we have been specifically told that it is about MTD. For mice at least, they were able to get the same amount of dox from ava6k in the blood as from naked dox, but as a consequence there was then ~18x more dox in the tumor (with ava6k vs. naked dox). So while ava6k is very targeted there is enough FAPa in the system to eventually lead to an MTD.

In case anyone wants a quick list of those to bin (i.e., non-contributive) here is my current list (perhaps a bit historical...and I'm sure that the same people are represented multiple times on the list):

prionace

Ray.Thirtle

Ndn71

Ajok

mortgagefreeman

Rollyroll

AgentB

Sangijuelas1

sophie98

richar

Wressmycash

wyndrum

Toukankahmoon

Systemzero

Viking.Raider

Thornogson

Revoy

Joe_Bloggs_

truant2tb

tiger29

JoeSoap1

Bottmzup

TerryMC1

@PL, yes, it was an interesting idea, which led me digging for the ratios and whether they were dependent on the ava6k dose level. It would square AS's and Prof Twelve's comments, and of course we don't know what they are seeing in C5, so everything is still potentially on the table. But from the dox ratios, I think we're still in the 'linear regime', and AS is just being optimistic with timelines.

A slight correction about MTD and the mechanism of action of ava6k. There isn't a "finite amount of FAPa" in the tumor, in the sense that FAPa isn't destroyed when it meets ava6k. When an ava6k molecule meets a FAPa molecule, ava6k is broken down into dox and the leaving group, and FAPa remains unchanged. Hence it can then cleave another ava6k molecule.

When ava6k is injected into the body, it is essentially inert, so it will keep circulating in the system until it is either excreted, or it finds a FAPa molecule. The FAPa molecule may be in the tumor, or it may just be 'systemtic' (i.e., somewhere in the body, doing its normal thing). So even if all the cleaved dox in the tumor stays in the tumor, when the level of ava6k is increased, more dox will be in the blood because more ava6k will find systemic FAPa. You can see this on slide 84 of the SD presentation, that the higher the dose of ava6k the more dox was found in the plasma.

Other than the first cohort (not sure what happened there), you can also see on the slide slide, that the amount of dox in the plasma/tumor (dox ratio) is *not* a strong function of ava6k dose level. This means that the same fraction of dox is released in the plasma as in the tumor (roughly 90-to-1, which is incredible). This emphasises just how much FAPa is overexpressed in the tumor for these patients.

The takeaway (for me anyway) is that MTD will happen when enough dox is released by the systemic FAPa. And given the ratios seen so far in human (and the results from the mice) I don't expect that to happen for quite some time.

Possibly lda. i think the push to get on to p1b will just be too strong, though.

good point about the biopsies, c5 levels could be off the scale. but even more useful would be straight dox comparison biopsies.

Yep, that’s my guess.

My guess is that c7 will end without an MTD found (based on Prof. Twelve's comments at the SD and on what we saw in the mouse models and scaling accordingly).

I hope that we hear about c5 finishing and c6 starting soon, but i think we need to be prepared for a few weeks/month slippage. Back when the trial started (Aug. 2021), AS mentioned that they would have gone through multiple cohorts by xmas of that year. In the end, c2 didn't start until Jan/Feb 2022. So he's always a bit optimistic on the timings of the cohorts. Of course we're in a new regime now with many more UK sites and the US sites online, so that should accelerate things.

I don't think that they are presenting (please correct me if I'm wrong)...just attending.

According to Mr. Google, average Phase 1 oncology trials cost ~$4 million and phase 2 costs ~$13 million. So definitely easily in reach with any licensing deal (and even potentially without).

https://www.sofpromed.com/how-much-does-a-clinical-trial-cost#:~:text=The%20average%20cost%20of%20phase,median%20of%20%2441%2C117%20per%20patient.

Could be, but it is not a given that 3 patients were dosed on the 5th. Patients are generally dosed if and when they qualify...so it's not like you qualify and then they make you wait a couple months before beginning. I don't think that we can work out timings exactly, other than to use previous cohorts as a guide...where obviously C3 was the shortest so we hope that is reproduced now for C5.

And I would be very surprised if MTD was found in C5, based on Prof. Twelves comments during SD.

Well said DTW. It explains how the SP is at this level, despite the multiple amazing news drops over the past few months. Comparing Avacta with biotechs on reasonable exchanges (i.e., Nasdaq) you see that there each time the product is derisked, the SP increases accordingly. Prometheus is a good recent example. Of course only the final price (at BO) matters for the LTH, however, under normal circumstances it is nice to see the SP rise to give confidence in ones convictions. After believing that the SP would re-rate after a number of news drops, it's now clear to me, that news will not drive this share. Only licensing or a BO offer will move the price significantly (i.e., to where it should be today...in my opinion >400p).

The good news is that for large pharma companies, the price they offer is not linked to the current SP. It is based on expectations of future sales and competition within the market for the new product (i.e., a bidding war). But until then I believe that we simply have to brace ourselves for frustration in the SP. (to be clear I expect the SP to fluctuate between 1 and maybe 1.7 pounds over the next few months)

@hh, yes you are correct. But the cell killing effect will be the same in vitro or in vivo. To be fair, this only gives us a bit more info that we already had. However, it does add (to my mind) significant confidence to the IC50 values quoted by Avacta on slide 84.

Icecool, that is fantastic stuff, thanks a lot! This is exactly the info that I was looking for. What level of dox is typically found in tumors when given as straight dox. The numbers that Chat GPT jive pretty well with those given in the lower table on slide 84 in the SD presentation. The take away message is that in C4, there is already ~3-5x more dox in the tumor than is typically seen when giving straight dox. This is very similar to that seen in the mouse models.

So 3-5x more dox in the tumor, 3-4x less dox in the blood. This is a monster drug in the making.

Is there any chance that Chat GPT can give the references for the numbers (i.e., IC50 range of colon cancer)? At these levels, there is no way that the clinicians wouldn't already have seen some serious benefits of ava6k.