Member Info for jive_turkey

Well said BV. You may want to copy that, as it is a succinct response to an issue that keeps coming up.

@RD, I'm not sure where the fantasy comes in. The assumptions were pretty clearly laid out. The big one is no dosing holidays, but as has been stated, if there aren't serious DLTs observed, I don't see why a dosing holiday would be given.

And by the way, in response to the FUD spreading crowd:

"Progression-free survival (PFS), the time from treatment initiation until disease progression or worsening, may be used as a direct or surrogate measure of clinical benefit for drug approvals."

Taken from this paper: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6636299/pdf/jcav10p3717.pdf

One potential issue is that by changing the dose level, you will be adding complications in interpreting patient outcomes. I'm assuming that the patients still on ava6k are still 'part of the trial', i.e., their progress, side effects, cardiotox, etc. are still being monitored on a regular basis. Ideally, even with a relatively small dataset, they may get an estimate of the progression free survival rate as a function of dosing level. Yes, it will have large uncertainties as the statistics (i.e., compared with ~60 patients all with the same tumor type), but each patient will have been evaluated prior to dosing about life expectancy. If it is seen that say C3 and C4 patients are more likely to have PFS and the fraction goes up in C5, then this would be, yet another, very strong sign of efficacy. And if they have kept the dose constant (i.e., once you start at a dosing level you remain at that level) this data is already in hand.

My point is that for the statement from AS, it is not relevant whether 25, 50, 75, or 100% of ava6k is cleaved. He is comparing the amount of ava6k injected to that of naked dox, with only the conversion for molecular weight. So already in cohort 2 the patients were receiving more dox (in this sense) than allowed with straight dox. He has used this way of describing the doses since the trial began. So the usage in the RNS was not ambiguous, it follows from previous presentations.

And if we use the appearance of side effects as a broad indicator for how much dox is being released (as the tumor makes up a small fraction of the body weight, I assume that in absolute numbers not that much dox is being released there - but in relative concentration it is huge) then I would imagine that even in C5 there is 'less dox' released from ava6k than given in a 75 mg/m2 naked dox dose.

@BV, yes, sorry I didn't mean to imply that this was a call from the Fred Hutchinson for P1b. I agree it is for P1a. But it is interesting that this is a call for a specific cancer type. And of course it may feed into P1b.

You may be right about P1b, that's exactly what I had been thinking until this morning. They definitely could split the 60 ava6k patients between STS and breast cancer, but of course then the statistics go down. So it's a trade off. Or they have two P1b trials going at the same time, one for STS and one for breast. Will be interesting to see.

Also note, that once a drug is approved for a given condition (say STS), the trials to get it approved for other conditions are often much faster and require less patients, because you no longer need to measure safety (at least not as much), it is much more about whether the drug is efficacious on the new condition over standard of care.

Hi BV. As for (i) I think that what is meant is that more dox is given through ava6k than standard dox. i.e., we don't need PK data to state this, it is just accounting for the differences in molecular weight. Of course PK data will tell us how much cleaves and biopsies will tell us how much more dox is in the tumor than if given by naked dox.

(ii) I agree. They've dropped this hint a couple times recently, would be fantastic.

(iii) The absolute level of FAPa present isn't very important. It is the concentration of FAPa in the tumor and in the rest of the body. If the concentration is higher in the tumor, ava6k will always be better than straight dox. If it is lower in the tumor than in the rest of the body, it will be worse than straight dox. Dox is indeed a very powerful chemo and the results should be pretty damn amazing in P1b (and likely P1a). However, after seeing the ava3996 poster and presentation, and having it referred to as a "tumor agnostic" treatment, this is starting to sound quite like a cure.

The top 4 cancers in the UK (and the west in general) are in order: 1) Breast, 2) Prostate, 3) Lung, 4) Colorectal. All 4 are high in FAPa. Also, all 4 are treated (at different lines...most typically not as a 1st line) with doxorubicin.

Avacta have stated previously that they will likely select between 1 and 2 cancer types to focus on for P1b. Given the change to the P1b protocol (direct comparison with dox, and taking 2 dosing levels), I think many of us assumed that we would chose just 1 cancer type, and Soft Tissue Sarcoma (STS) was the obvious choice (dox is standard of care, but not overly effective, low survival rates, orphan drug designation, etc).

However, as posted by Tom on twitter (and gmcc here) there is an open call at the Fred Hutchinson Cancer Center in Seattle for participants with Advanced Breast Cancer.

https://www.breastcancertrials.org/bct_nation/mts/mtsResult.seam?zip=94107&searchTerm1=NCT04969835

Could it be that STS and Breast cancer will be the two tumor types chosen?!? That would be a bold move, as there haven't been any breast cancer patients (at least in C1-C4). But dox is used to treat breast cancer in some cases, and it is high in FAPa, and if they see general efficacy, it may not too crazy.

Breast cancer treatment is expected to reach $55 billion per year by 2027 (yes, that is right, $55B, it is now over $30B)

https://www.fortunebusinessinsights.com/industry-reports/breast-cancer-therapeutics-market-100163

Selecting STS and breast cancer for P1B would be a masterclass in drug and commercial development. Maybe we get some hints at the AGM...or more likely, we'll still need to wait a few months, but this could be something to behold.

And i think this finally puts to bed the question of whether the trials will need to stop at 450 mg/m2, i.e., the maximum lifetime dose of straight dox. They are clearly able to blow right past this, as it is so targeted. So they must be measuring the amount of dox in the plasma in order to make sure they are below this lifetime limit.

The slides on the SD presentation and subsequent presentations still referred to a 3 week dosing schedule. However, AS and others have floated this idea a few times recently (without the side effects you don't need to wait 3 weeks between dosings), so I wouldn't be at all surprised to see a change format for P1b when it starts.

Yep, still thick as mince.

@RAH, i guess dox will behave like dox, who would have thought?

From the SD and subsequent presentations I’ve seen that 19 patients were included in C1-C4, but 22 were dosed. I assume that the difference is due to 3 patients being removed from the study due to unrelated events (remember, these are terminal cases.

So C5 dosed 7 patients, but we don’t know how many will be included in the final cohort numbers. Based on previous cohorts i guess 6, and 1 removal.

Like many here, I have been dumbfounded by the market reaction to Avacta's amazing results over the past 4 or 5 months. Here is yet another example of what I would describe as a reasonable market reaction to a company.

In Oct. 2022, Dice Therapeutics released Phase 1 results for the lead drug DC-806, a new drug for psoriasis. These results were typical Phase 1 results, i.e., nothing of efficacy, only basic safety and a general confirmation of the mechanism of action. On the back of these results the SP jumped by ~100% and stayed at relatively high levels. Phase 2 started in early 2023 and no results (to my knowledge have been released). Dice were bought out this weekend for a further 40% SP increase.

This is a novel drug that is likely a few years away from approval and many years before taking over the market. Yet the company was valued in the takeover deal at $2.4B.

Dice are further away from approval, targeting a smaller total market and at a similar clinical stage (Phase 3 is required for Vice, not for ava6k). They have been valued at ~7-8 times that of Avacta. Bonkers.

Neut, spot on again. Speaking with oncologist friends (not clinicians though, just academic researchers), dox is expected to be very effective against many cancers (as it has a generic killing mechanism...essentially against all dividing cells). It isn't used often (or at least only as a secondary treatment) because of the nasty side effects. So doctors need to mix and match different chemos to maximise on-tumor destruction and minimise off-tumor hits.

This is where the mind boggling numbers come in. If ava6k just replaces dox, we're looking at a $1 billion market at minimum, ~$3 billion if they can give 3 times the treatments, ~$5-10 billion if they can expand the patient pool...all assuming that ava6k costs the same as dox. Now, you add in patients that would normally get a different chemo because dox is too toxic for them (hits the body too hard relatively to the tumor - e.g., lung, breast, pancreatic, bladder - all FAPa rich) and you get another multiplicative factor.

Ok great. But now throw a tumor agnostic treatment in, again with little or no side effects, ava3996. And with these two, you've captured a major fraction of a $60B market (and may even grow it). It's easy to see the upside potential here...and at least with ava6k we are ~2 years away or less from full approval if things continue to go well.

Great point Neutronic. Getting biopsies from straight dox treated patients (as they have announced they will do) will provide a direct comparator. However, from what we've seen in rats, I think that there is a very good chance that this much dox (or at least this much for this long) has never been in the tumor of a live patient before.

Whoops, early/mid '24 is what i meant.

Thanks for the timeline RAH. For what it is worth, I assume that Avacta will apply for breakthrough designation once P1a ends (i.e., MTD is found or the biological dose is determined). This will be before the period when Lartruvo was applied for/granted, however as stated often, ava6k isn't a new drug, it is "just" a delivery mechanism. So things can be accelerated.

It will be clear to the company and clinicians if ava6k is working already (especially as expectations are that it should be more efficacious than straight dox...and we know that the side effects are much improved)....although of course that doesn't mean they don't have to finish the trials and get the relevant statistics, etc.

I don't think they will RNS the application for breakthrough designation (just like they didn't for ODD). Instead they will RNS the approval.

My guess for the timeline is then: P1a finishes in Aug/Sept, P1b starts ~6 weeks after that, breakthrough designation ~4-6 weeks after that, and limited approval for use (likely just STS at first) at the end of P1b. Again, P2 will still need to be done, and effectiveness on other cancer types will need to be shown, but some patients should start seeing a better cancer treatment in early/mid '23, I reckon.

There must be some reason (proceedural or scientific) why the can’t run P1a and P1b in parallel. After ODD and the opening of the US sites (as well as the responses during last Q&A, and change of P2) , I’m confident that mgmt have things in hand and have plotted the best possible path to approval. I’d love to know the detailed plan though…

@BV, good points. It looks like there are commercially available PDX models for a large range of common cancers (search Crown Bioscience PDX Models for a list of 30+). And I agree that dox likely works on CRC (we know it does in mice), it just isn't normally used due to toxicity. All the more reason to be excited about the large patient population in C1-C4 with CRC.

Yes, I was wrong yesterday, only 2 of the 19 C1-C4 patients had had any previous Anthracycline (likely dox) treatment. And I agree with you, this is to make the readout as straightforward as possible (i.e., all DLTs or cardiotoxicity would likely to be due to ava6k and not previous treatments).

Given that CRC isn't typically treated with dox, it is remarkable that it was chosen for the PDX mouse models in the first place. Shows confidence...and the results were "black and white" in mice. I'm optimistic they will be for humans too and P1a may just show this.