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A quick comparison between pre-clinical results of ava6k and ava3996.

You can compare Cmax and AUC (area under the curve for concentration vs. time) from the poster just released to the ava6k poster last year. Both posters compare avaXXXX vs. the standard drug (i.e., naked drug, either dox or ava2727D). For ava3996, the AUC was ~2-3% for the precision version vs. straight version. For ava6k, this was around 11-16%.

A similar result can be seen for Cmax (maximum concentration). ~0.3-0.6% for ava3996 and 2-3% for ava6k.

Conclusion: somehow ava3996 is even more selective of the TME that ava6k. Even more precise, by a significant amount, by about a factor of 5. It gets better and better...

@trading4good: good spot. Like you, my first reaction was negative on this. I mean, why compare to another drug where you do worse? The reason is that Trametinib only works effectively on tumors that show a very specific gene mutation. On these kinds of tumors it is extremely effective. So showing that ava3996 gets close, is quite the brag. However, requiring this specific mutation is the polar opposite of being "tumor agnostic".

@Kong. Yes. In the sense that the warhead (dox vs. Proteasome inhibitor) is better than dox. As Timster just reminded us, the key phrase is "tumor agnostic" from the recent interview.

Just to re-iterate: ava3996 was the primary precision candidate for quite a while. It was then switched to ava6k. This was a fantastic move, even if ava3996 proves to be more effective. ava6k only requires phase 1 and 2, while ava3996 will require phase 3. ava6k proves the platform which would be harder to argue for ava3996 (i.e., it may have cleaved but not been extremely effective for one reason or another). ava6k is the pathfinder. and the path has been laid out, exquisitely.

It's good. Pretty damn good actually.

The take away for me, go to the 2nd point in the summary: Ava3996 is activated by FAPa (no surprise there, we know Precision works). However, the 2nd sentence: this activation elicits cell death. Then have a look at the 1st point in the summary. "No safety issues are apparent."

Summary: Avacta have achieved the seemingly impossible. They have a Proteasome inhibitor that works on solid tumors with little or no safety concerns. Unreal.

Yes ava6k is going to be revolutionary, and is a massive step forward in cancer therapy. However, this is something else.

The main treatment that Prometheus is developing is for ulcerative colitis. Ulcerative colitis had a total addressable market size of $6.2B in 2020.

The total addressable market of ava6k is easily >$5B (as AS stated a few years ago), and my guess is >$15B.

It's an interesting case. The stock price double in December on the back of good clinical results, and the buyout price was double that again. Also, no increase over the past month, meaning this buyout was well and truly out of the blue.

DS, I don't think anyone is expecting a large SP change due to the poster (especially as these are pre-clinical results). The optimism comes from the expected accompanying video by the CEO explaining the results and commenting further on the ava6k trial. Followed the following week by the presentation of the annual results, which usually contains a few nuggets to get exciting about and potentially more detail on the route to market, both timescales expected size of market.

Given how much info was considered "non-material" for science day, I don't expect an RNS on monday. Would be great to get though...

Indeed biopsies to be key. Yes, of course they have to run the full trial to prove efficacy, and yes, that will take some time. But in reality, to know just how effective ava6k really is compared to standard dox, all they need to do is take a handful of biopsies in the ava6k arm and the dox arm. This is simply a direct comparison. Go back to slide 84 in the masterdeck. We know how much dox is in the tumor with ava6k (although ideally we'd like to do it like-for-like with the same type of tumor). We know that these levels are above that for therapeutic effects. We also know that there is significantly less dox in the blood with ava6k than naked dox. So all they need are those two numbers, the concentration of dox in the tumor from ava6k and from straight dox. If it's higher for ava6k, we have a blockbuster. If it is roughly the same or a bit lower, we still have a very effective drug with drastically reduced side-effects.

So they will know in the first weeks of P1b just how good ava6k is. Of course, we (PIs) won't know, but we'll likely be able to work some of it out based on the companies actions (just like we could infer that "it works" before they officially announced it).

Thanks for the paper RAH, fairly depressing reading. Imagine being able to expand someones expected lifespan from 18 months to 36 or 44 months, and without affecting the quality of life. Would be amazing.

@Neutronic - I don't know the answer to question 1. If they are chemo based, my understanding is that it all comes down to the specific patient...does the chemo kill the tumor faster than it kills the host?

As for your 2nd question, yes, the current use of dox is largely limited by toxicity. i.e., for many tumors dox kills the host faster than the tumor. So if you can remove the toxicities, I think that a number of other tumor types will be treatable with ava6k. I've posted before that colorectal cancer (CRC) is *not* normally treated with dox. Yet, that is the tumor type that Avacta used in the mouse models, and we know that it was extremely effective for that. So yes, once ava6k is approved for STS, I imagine that it will be rapidly adopted in the treatment of a number of FAP-rich tumors, like breast, ovarian, pancreatic, lung, etc. Probably alongside other treatments.

One thing that AS emphasised in the recent interview, was the mechanism of action for ava3996. This looks like it could kill any cell that it comes in contact with. ava6000, on the other hand, is only really effective against cells that are replicating. Some tumors grow/replicate faster than others, and these will be the obvious ava6k targets. ava3996 should clear up a large fraction of the rest.

I am not familiar with the mechanism of action for the other precision drugs in the pipeline, i.e., if they are different enough to offer benefits over ava6k and ava3996. We'll see. But TMAC will be the next big step forward, although I admit that I don't really understand the affimer based treatments (ava021 and ava028), but they don't use FAP to activate, so perhaps they are designed to go after the non-high-FAP tumors?

FWIW, here are my thoughts on why STS (following on discussions on this over the past few days).

Originally, when discussing ava6k, Avacta often referred to pancreatic cancer as a potential target, and often mentioned breast cancer and ovarian cancer for highlighting the commercial opportunity. However, looking back at some of the old presentations, STS was always there as well. Presumably, this was because STS is a relatively rare tumor type, so the commercial opportunity is relatively small (compared especially to breast cancer, which is a $20B+ market). So you wouldn't highlight this tumor type as your main target, *unless* you received Orphan Drug Designation (ODD). Since ODD is far from trivial to get, it would have been a very bad strategy for Avacta to say that their goal was to get ODD, because if they didn't (for any reason) it would be seen by the market as a failure. So until ODD was attained, it made sense for Avacta to highlight other potential tumor types.

But then they got ODD and things changed. So why STS? One big reason is that, unlike the other tumor types, dox is given to STS patients as a *first* line treatment. For all the other tumor types, dox is used after other treatments have been tried and have failed to provide a robust response. And if you are looking to test a new drug, and find all associated side effects, your job will be much much easier if the patient hasn't undergone previous treatments.

Another big reason is that ODD, by itself, offers a number of commercial benefits. Tax breaks, trial help, etc. This seems also like the best way to get into the system, i.e., to set ava6k up well for breakthrough and fast-track status.

Once approved, ava6k can also be prescribed/used "off-label". i.e., used for other tumor types that it hasn't explicitly been tested for. Hence, going for STS 1) likely speeds up the route to market, 2) will provide a >$1B market pretty much from day one (i.e., the whole STS market, multiplied by >3 for the additional doses on offer and for expanding the patient pool), and 3) will likely not delay its use in other tumor types by too much (it can be used for other tumor types while clinical tests are ongoing).

Also, I strongly doubt that Avacta applied for ODD based on one STS patient in C3. Applying for ODD takes months of work, and there simply would not have been enough time to see the results and decide to write an application. This was clearly in the pipeline all along. That's not to say that they wouldn't have studied this patient in detail and may have even included some preliminary results of the patient in the ODD application. It just wasn't the trigger.

Hence, getting ODD and changing the layout of P1b are amazingly bullish indications that Avacta are taking this to the big time.

I'm with you Timster. I rewatched the interview from last week this morning, and I really like this quote from Alan:

"Quite a few people assume that you are releasing dox in the tumor, therefore it must be efficacious. Right? Because it's dox. And the fact that it is an approved drug should give us a high degree of confidence in seeing efficacy. But that is not good enough from a regulatory perspective, you can't assume that, you have to demonstrate in a human trial the efficacy. So absolutely we should have a high degree of confidence because we are releasing a known drug that is efficacious in soft tissue sarcoma we have to go through the P1a and P2."

Summary: yeah it works, and yeah it is efficacious, but we still have to jump through the regulatory hoops. Pretty damn clear.

Spot on PL.

While the Moderna cancer 'vaccine' is great news in the fight against cancer (and I am invested in Moderna), the recent news reports are a bit misleading. We are familiar with vaccines that prevent us from getting a (serious) infection, i.e., you get a measles vaccine in order to not get measles in the future. However, this is not how the cancer vaccines work.

The cancer vaccines must be made for each individual patient. Once you have a tumor, they can analyse the tumor to find some specific proteins that are only found in that tumor. They then create a vaccine to train your body to find and destroy cells that host these proteins. It is a treatment, rather than a prevention. The tailor made aspect of this approach (which has been found to be very effective in melanoma) means that it is always going to be expensive and not well suited for scale up to large populations. Hence, this is great news, but definitely will not replace large scale treatments like chemotherapy.

https://www.gavi.org/vaccineswork/modernas-experimental-cancer-vaccine-treats-doesnt-prevent-melanoma-biochemist

@Kong, yes, I think that they will continue to C6 and C7 if an MTD isn't found (and likely 300 mg/m2 and 250 mg/m2 as you suggest). I agree with others that the adopted dose is likely to be the one used in C3 and C4, but as has been noted, the FDA and other regulatory bodies push hard for a known MTD in order to see the full range of the drug (even if the final dose won't be near the MTD).

But there may be some additional complexity for ava6k that doesn't apply to standard chemotherapies. I could see that the typical dose being say 200 mg/m2 for 12-18 cycles, which would apply to most patients. However, for particularly aggressive strains of cancer in otherwise healthy individuals, I could see them going for higher dosages (perhaps near MTD) to try to bring the growth under control. This may explain the two treatment arms in P1b.

@Kong, yep, at the highest ava6k dose level, there was 100% survival in the mouse models after 6 months. In the lower dosing level, it was 90%.

FWIW, I agree with BV and Wiggly. Based on the data to date, I think that the clinicians will have a pretty good view on the efficacy of ava6k. Not proof and definitely not enough to state publicly. However, a good view. As more STS patients are dosed, this will only become clearer. But BV is also right. We won't hear anything about efficacy until the end of P1b. That is when they will have the statistics to back up any claims.

Yes, most to all. But the key is that dox is only used for a relatively small number of targets, not because it isn't effective, but rather the side effects are too great. Remove the side effects and you will be able to use ava6k on a much broader tumor range than straight dox.

The mouse models had colorectal cancer, which is not typically treated with dox. However, ava6k worked wonders on those little guys.

RD - remember that for the mouse models there was ~3 times more dox in the tumor for ava6k than standard dox (for the same dose level). So you're right, we should assume 100%. It should be 300%.

~3 times more in the tumor and ~4 times less in the blood in mice.

G'morning BV. I don't think starting to recruit in the US is worthy of an RNS. However, when the first patient is dosed in the US is when I expect an announcement to be made.

Following GMCC's example about contacting AS directly (thanks for sharing the email address GMCC!), I took the liberty to email AS to ask him more about page 84 in the slide deck. Specifically, I wrote that I could find the level of dox in the plasma from a straight dox treatment (after 24hr), so that I could directly compare to the results from ava6k (I posted this a few weeks ago, the result is that there is 3-6x less dox in the plasma when using ava6k compared to straight dox - for a given dosing level). However, I could not find any papers discussing the amount of dox in tumors after 24 hours(from straight dox) so that I can't compared ava6k's results to straight dox, which also means I can't compare the plasma/tumor ratios in the next column to that of straight dox.

To my surprise, AS replied within 24 hours, very cordial and helpful. I won't post his reply here, but there were three main points. 1) that the data for straight dox from biopsies is not available in the literature, which is why no comparisons were given. 2) that this is one of the reasons to add a straight dox arm to P1b, so that they can get some of this data themselves. His third point was that while it is academically interesting to know the comparison of dox levels from straight dox to ava6k, it is not really the key. The main takeaway, in his opinion, was the comparison with the dox levels (ava6k) in the different cohorts with the smaller table below, which shows the dox levels necessary for different modes of cell killing. This shows that "we are getting enough doxorubicin in to the tumour regardless of what the amount would have been with a straight doxorubicin administration".

So, just like FMcL, the focus is that getting dox into the tumor is the key, after that, dox is dox. The conclusion is that they are delivering "enough dox" into the tumor, and they are seeing drastically reduced side effects. Sounds like a winner to me.

I, for one, am looking forward to next Thursday ,so that I can top up the old ISA.