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In the SD presentation we were told there would be three arms to P1b. One arm will be straight dox as a comparison, and then there will be two ava6k arms. There will be two dosing levels. It is conceivable that arm 1 will be at 200 mg/m2 (i.e., the C4 level) and that arm 2 will be at a higher dosage (closer to MTD). If that has already been agreed, then P1b may already start with arm 1, while P1b of arm 2 will need to wait until P1a finishes. This is one way that P1a and P2b could partially overlap. As has been noted by others on the board, there is precedence for this.

Great post DTW. Worth remembering, however, that ava6k was effective in treating (human) colorectal cancer in mice. Once you remove the worst of the side effects to allow higher/longer dosing cycles, it seems that dox is quite effective on a much larger population of tumor types than it is typically used for.

11 out of the 19 patients dosed with ava6k so far have had colorectal cancer. Typically colorectal cancer is not treated with dox (or other anthracyclines). So naively we wouldn't expect to have seen a strong effect on the tumors of these patients. However (and this is a big however), if we look back to the pre-clinical results (i.e., the mice models), the cancer used was in fact a human colorectal tumor. Think back to that powerful image, showing the mouse liver with and without ava6k treatment. The tumors present were liver metastases of colorectal tumors. And remember that these were human derived tumors.

The take away is that, in fact, we do expect efficacy in colorectal tumors with ava6k, based on what we've seen in the mouse models. However, it is important to note that the median patient has only received 2 doses of ava6k, so we may not expect a major impact on the tumors yet, especially in the early cohorts (lower dosages). The effect should become more pronounced with more cycles of treatment.

While the P1a trial is focussed on safety and tolerability, the above suggests that the scientists running the trial will have some insight into efficacy. The small number of patients and small number of doses almost certainly mean that this will not come anywhere near the scientific standard of 'proving efficacy' (no one would stake their reputation on the results, and certainly the company wouldn't either). However, there is likely to be some evidence to clear the much lower bar of generating excitement/hope amongst the scientists and company.

I, for one, find it difficult to believe that it is just a random chance that the majority of patients in the trial display the exact tumor type used in the pre-clinical study. Also note that they highlighted the liver metastases in the biopsies and the 'tumor free' liver in the mice treated with ava6k.

Good summary BV, and I'm glad you enjoyed the book!

Thanks BV. If "ava6k does what is says on the box" (i.e., strong chemotherapy with limited side effects allowing many more cycles) as Prof. Twelves said, then these are all in line to have the standard dox treatment replaced by ava6k. My understanding is that different tumor types react differently to specific chemotherapies. The side effects associated with all chemotherapies are very bad, so you want to choose the chemo that has the largest effect on the tumor for a given effect on the host.

From what I've read, dox should be effective for a large fraction of solid tumors. It isn't used more often (although the list of tumors that it is used for is relatively long) simply because of the side effects, and other chemos do more damage to the tumor for a give amount of damage to the system. Hence, if you remove/significantly decrease the side effects, you open the possibility of using precision dox for a much wider range of tumors. Of course this still leaves room to develop precision forms of other chemos, but my view is that precision dox is going to replace much of the dox use (e.g., fap-rich STS, breast cancer, etc) and become a standard treatment for a number of other (fap-rich) tumor types where dox isn't currently used.

For your example of pancreatic cancer (one of the tumor types Avacta originally suggested as a target), the 1-year survival rate after diagnosis is only 25%. And after 5-years its just 5%. This shows that current chemo doesn't have that large of an effect, i.e., you'll need more of the drugs to kill the tumor and in so doing will kill the host. Drown the tumor in ava6k however, and the patient has a fighting chance.

Great post DTW! Another one that I really liked:

"This drug (ava6k) does appear to be doing what it says on the box" - Prof Twelves (after FMcL's talk)

Anyone else feel that we should be putting Prof. Twelves out to give these talks in the future? No offence to FMcL and Andrew Saunders, but he brings a level of excitement and optimism (along with gravitas) that wouldn't go amiss.

One correction - it is the dashed line in the paper I linked, not the solid line.

@PAH, indeed at the time of infusion, for straight dox it will be more concentrated in the blood than in the tissues. However, dox diffuses into the tissues extremely rapidly (half-life of 5 minutes if I remember correctly from a post from Ophidian some months back). Hence, the two (concentration of dox in the plasma and in the tumor) should become similar very rapidly, definitely before 24 hours has passed.

Like many on here, I have found the SD presentation extremely valuable, but at the same time, a bit too technical to really wrap my head around. In the absence of a simplified presentation from the company, I decided to do a little digging. In particular, I wanted to know how the numbers presented on page 84 (amount of dox in the plasma and tumor at 24hr after infusion) compared to straight (aka naked) dox.

From the ava6k trial, we see ~5 ng/mg of dox in plasma for cohort 1 and 10-15 ng/mg for cohort 4 (nicely showing larger amounts of the drug in the blood for larger doses). Prof. Twelves also emphasised in the Q&A that this was real dox, not any metabolites.

Ok, great. But how does this compare to naked dox? It turns out that our own Prof. Twelves had a paper from 1991, where he showed the level of dox in the blood as a function of time, with a reference dox dose of 75 mg/m2 (https://link.springer.com/content/pdf/10.1007/BF00685539.pdf - Fig. 1 the solid line). He finds that at 24 hours, there is 30-40 ng/ml of dox in the blood.

In C4, the patients got the equivalent of 135 mg/m2 dose of dox, which is 1.8x the reference 75 mg/m2 dose that Prof Twelves used. Yet, even at this dosage, the patients at 2-4 times less dox than straight dox. Normalising out the different dose sizes, we see that there will be 3.6 - 7.2x less dox in the blood, using ava6k instead of straight dox.

The question now is (which I am finding very difficult to answer through google) is how much dox in the tumor do we expect for straight dox. Is it the same as in the plasma? This is something that someone in the company should have simply stated, as it must be pretty common knowledge in the field. However, from what I can gather (although if anyone knows better please tell me) from comparing independent papers (some measuring dox in the plasma and others in the tumor) that they are the same, or at least similar. This means that the ratios presented on page 84 *can be* compared directly to the mice models.

The take away message is that for a given dose of ava6k, there is 3.6x - 7.2x less dox in the blood compared to naked dox. At the same time, there is 85x (median) the amount of dox in the tumor than in the plasma. The results presented on SD then clearly show the double effect: less dox in the system, more dox in the tumor. Boom.

Now that is a result worth highlighting.

(also in all my digging there were a number of papers that explicitly stated that the higher the concentration of dox in the tumor, the better the cytotoxic activity within the tumor so that is a non-issue despite what the FUDers claim).

@RAH, agreed.

@BV, good point. As dox is the standard of care for STS, I guess for P1b, they are unlike to be anthracycline naive. But it is stated by Prof Twelves in the question session after Dr. Saunders' talk, that perhaps in P1b and P2, that patients may be offered ava6k before dox (i.e., they forego the standard of care) as the saftey profile is so good. Exciting times.

On slide 85, it states that Avacta expect 20 US & European Investigator Sites for Phase 1b. Wow! That is a huge increase over the previously estimated 6 UK sites and 2 US sites. This massive increase suggests extreme confidence. Why do this? 1) to accelerate the patient numbers and 2) spread the word far and wide about the potential of ava6k and precision.

That statement was from a few years ago, when the plan was to license out ava6k. That strategy has been changed, as laid out by AS during the AGM last summer. The plan now is to keep ava6k in house (i.e., no license deal) and license out other drugs coming up behind ava6k. Many, including myself, assume that this means ava3996.

When, and if, the ava3996 deal comes through, is anyone's guess. Presumably it will be sooner rather than later, given the need for funding the P1b part of the ava6k trial in the near future (something that wasn't included in the funding round last fall). This is the most straightforward way to fund the continuing ava6k trial (through the license of ava3996).

And in terms of price, given 1) the scale of the market for ava6k (with potentially increased efficacy and significantly reduced cardiotoxicity) and 2) the *in human* data now in hand showing the MoA works, I don't think 10x the 25M price is anywhere near the value of the drug (maybe this applies to ava3996, although i would also argue that this would be on the low side, now that we know the MoA works). 100x or more is probably closer to the value being sought. 250M would be closer to promising *pre-clinical* drugs.

BITL, I think that sums things up nicely.

@PL, yes, that's my take. But I don't have the foggiest as to the cause of the delay then...unless it is to change some other part of the protocol...

From BITL "Dox concentration is measured by systemic exposure to cleaved dox. HUGE news."

Agreed! Effectively, the trial isn't limited by the amount of ava6k put into the patient, but rather by the amount of dox seen in the blood (or perhaps inferred from the urine).

Just back from a weeklong trip, quite jet-lagged. But fantastic to come back to these great results! Overall, i agree with BITL, the data look very good, exactly what we were looking for. The AUC (area under the curve) reduction data are consistent between rats and humans, although the C_max results were a bit better in rats than in humans. As you note MrR, the increase in concentration of dox in the tumor and plasma with increasing dose level is very good news, it shows dose dependent results, which is a main thing to prove in P1a studies.

The presented results also show the complications of running a real-world human trial. Note that the median number of ava6k cycles per patient was just 2. So all the timing arguments that we've made (myself included) about how long until each cohort would be finished weren't correct. And on that point, note that cohort 3, which was the shortest duration, had 6 patients, so it seems that the number per cohort may simply be the number of patients ready for dosage at that time (with a minimum of 3). If they haven't started C5 or even chosen the dose level, then I think finding a MTD in the first half of 2023 is overly optimistic.

The side effects slide is powerful, amazing results. And probably the most positive point to take away for me, is that they are already thinking about the number of cycles that patients will receive of ava6k, 12-18, up from the standard 6 or less of straight dox. Even at baseline dox levels (of which we are 2.5x the baseline and going higher!) this increase in cycles would already lead to dramatic improvement in the patients.

And thanks to Wallyj for the notes on the presentations, i haven't had a chance yet to listen to presentations yet.

Finally, the ratios of dox in the tumour to plasma look extremely good. I don't know exactly how comparable these numbers are to much discussed 18-1 ratio seen in mice, as in mice it was from biopsies of the tumor compared to biopsies of the heart (which obviously you can't do in humans), rather than tumor to plasma ratio.

The results are looking very strong, definitely comparable to the pre-clinical mouse models. I do, however, find it pretty amazing that Avacta haven't put out a video summarising the results for PIs, like they did for the poster of pre-clinical data last April. This seems like a very easy thing to do, which would like have a significant and positive effect on the SP.

It's a quality video and shows the confidence of the company. But it is not made for general consumption, i.e., not for the public. This is made for specialists and specialist investors. Looks like it's going to be a great day tomorrow, but this doesn't imply that this will be going to main stream media in the coming days. I still think it will be either announced during a major oncology conference this spring or at the end of P1a. But with this, my confidence has never been higher...just a question of when, not if.

@Riesgo, yes, that is clearly stated on the webpage that this was from the preclinical studies. But it is fantastic that they are now drawing attention to it, as a general property of ava6k (i.e., you don't draw attention to pre-clinical studies when the human studies are performing worse). My guess is that for humans it is going to be around 20-25x the dox in the tumor than in the heart/blood.

@PAH - yes, I have assumed a linear scaling, which away from saturation levels, shouldn't be too bad of an assumption. But of course this is why clinical trials must be run. However, as for your AUC comment, I don't think I follow. For rats (which is the results we were shown in the poster last April) the ratio of AUC of ava6k and AUC of dox was 8.7....i.e., a very large difference.

RD: I tend to agree with you. My guess is relatively low dosage (although still higher than C4) to keep side effects at bay. However, i don't expect a 'low increase in efficacy'. In the mice models, the efficacy of increasing the dosage was quite striking.

At the risk of adding fuel to this discussion which is based largely around a misunderstanding, I'd just like to reiterate that the ratio of dox in the tumor to the blood is independent of the dose level, so it is irrelevant whether you use the weight of dox or the weight of ava6k (with the only exception if we are in a saturated regime) in the dose given.

Let's take an example of just straight standard dox. If a person gets 1 unit of standard dox, there is an equal amount of dox in the tumor as in the heart, so the ratio is 1:1. If a person gets 2 units of standard dox, there will be twice as much in the tumor and twice as much in the heart, so again the ratio is 2:2 = 1:1.

The same applies to ava6k. If a mouse gets 1 unit of ava6k, the tumor has 18x more dox than the heart, so the ratio is 18:1. If a mouse gets 2 units of ava6k, the tumor will have 2x the previous amount and the heart will have 2x the amount. So the ratio remains unchanged, 36:2 = 18:1.

Indeed, some of the presentation slides specifically say the dose level in dox and ava6k molecular weight unites (e.g., slide 14 of https://avacta.com/wp-content/uploads/2021/09/Avacta-Group-plc-Interim-Results-Final.pdf). And for some calculations, specifically trying to figure out the 'amplification factor' of using ava6k in getting dox to the tumor (i.e., more dox from ava6k ends up in the tumor than would be expected from normal dox because it keeps circulating in the system until it finds a tumor), the molecular weight needs to be taken into account. But for the ratio of dox found in the tumor compared to the heart (or blood) this is simply not relevant.

So in response to PAH, if ava6k works in humans as it did in mice, we expect a factor of 18x more dox in the tumor compared to the heart. But my belief is that the ratio is likely to be significantly higher than this...although perhaps that is just my optimism.

The question, of course, is: would it be better to keep upping the dose of ava6k to end up in the same level of dox in the heart as giving straight dox? In that case you'd have all the same side effects as normal treatment, but of course the tumor would be getting hit much harder with dox than the rest of the body. So same side effects, but much higher efficacy (dox in the tumor). Or, would it be better to give a relatively small amount of ava6k (which is likely to be higher than the C4 dose - as they have not found significant cardiotoxicity and implied limited other side effects too) which would still deliver a bigger punch than standard dox, but with little or no side effects. That is what the clinicians will be discussing and likely experimenting with.