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Definitely possible. My blind guess in the dark is 280 mg/m2 for the next dose.

BITL and I appear to have switched optimism/pessimism. I, for one, don't think we'll see much data regarding the ava6k trial at the science day. It's clear that the original idea was to present much of the ava6k data at the science day. This was when P1a was planned to be finished in the autumn of 2022. As P1a is now continuing until at least mid-2023 (which, don't get me wrong is a fantastic thing, showing just out targeted ava6k is) I think that we won't see much data until the end of p1a.

For the science day, my guess is that they will repeat the tag line from the last RNS and maybe provide an anecdote or two. So ava6k will be hailed as a success, but most of the time will be spent discussing 1) affimer therapeutics, 2) TMAC (maybe moving into IND enabling studies???), 3) other precision drugs (ideally we will hear the status/plan for ava3996 and maybe even the next drug in the pipeline) and 4) joint ventures in therapeutics (e.g., affyexell).

As for the AACR, I could see them sitting out this year. But there is a chance that they will use the opportunity to announce ava6k to the world. Or they may wait a year, until P1a and P1b are done and then use the stage to also present efficacy data.

Muck, seems like a possibility to me.

Thanks to Marian and SR on Twitter, this seems very relevant to the dosing level discussion:
https://twitter.com/SamJRobbo/status/1619083010241863687

As I have little interest in discussing gaps nor engaging with those not interested in actual information regarding the company and/or trial, I thought it might be interesting to discuss the trial design. Specifically, how the MTD could be found in the limited timeframe (by mid-year) that AS has suggested. My starting point is that, with mice models as a guide, we are very far from a MTD. We are currently at a bit of 2x the standard dox dose, and I suggest that MTD might be closer to 6, 8 or even 10x the standard dox dose.

I noticed that there are a few different ways to design a Phase 1 trial, with the standard design being a 3x3 type design, like the one Avacta are currently using. An alternative design is the "Accelerated Titration" (https://pubmed.ncbi.nlm.nih.gov/9262252/) design, which effectively uses 1 patient per cohort until some dose limiting toxicities are identified. The goal of this is to accelerate the completion of P1 and also to ensure that more patients are given therapeutically relevant doses.

Shasqi used this in their recent trial, starting with 1 patient per cohort for the first few cohorts, then switching to three...i guess when they though they might be getting near the MTD. I also noticed (https://www.shasqi.com/assets/pdf/2021-03-25_AACR_TIP_Poster_-_Final.pdf) that that Shasqi's dose escalations were huge, effectively going up by 1x the initial dose in each step (i.e., 1x, 2x, 3x, etc).

Maybe Avacta could change the design to 1 patient per cohort and up the dose escalation from the 40 mg/m2 used previously to 80-100 mg/m2. In that way, it is not unreasonable that they could get to 6x or more of the standard dox amount in the next 6 months.

For reference, check out page 14 of this presentation
https://avacta.com/wp-content/uploads/2021/09/Avacta-Group-plc-Interim-Results-Final.pdf

And for the weight conversion, note that 1 unit of ava6k is 0.67 units of standard dox (it's just the molecular weight difference)

@Thornogson - in mice they were able to dose 4x more (weight adjusted) dox with ava6k than dox on it's own. This led to 18x more dox in the tumor than the standard dox. An application factor of 4.5.

So not only is the dosing of ava6k much higher than standard dox, we also expect this to be amplified significantly in the tumor. So at a factor of 2x higher dose in humans, it is likely (assuming mice models are reproduced) that the tumor is seeing 9x the standard dose of dox. However, this is likely to be a lower limit, given the higher level of systemic FAPa in mice than in humans.

Unfortunately, "precision therapies" does not correspond to Avacta's "Precision platform". Precision therapies focus on gene editing, which is patient specific, in order to target cancer. So while it would be great for a large investment fund to get into Avacta, this doesn't fit their bill

Good question Stodge, I've wondered the same. After doing a little digging, and also following up on what BuenaVista and Ophidian have posted, I believe that the answer is that dox (or whatever chemo) would be flushed out of the tumor quite rapidly. Yes, some would be absorbed by the tumor, but much of the drug would leak out and cause damage elsewhere. So you need a chemical (for example SQL70 for Shasqi) that is able to stay in the tumor for as long as possible. If that stays in the tumor, then you can use it as a binder or enzyme for your prodrug, for the chemo to be released (relatively slowly) into the tumor over a number of hours/days.

There are only a couple of experimental treatments for specific cancers where chemo is injected directly into the tumor. This suggests that there is little benefit over injection into the blood stream, in most cases.

Since FAPa stays in the tumor always, it is a perfect enzyme to use to 'activate' the prodrug. ava6k can then keep circulating around the system for hours/days and each time some gets into the tumor, it interacts with FAPa and gives off some dex.
Simple and elegant.

That's right BV, but i think the question is why wasn't it 'activated' in the other 5 candidates. Obviously the company hasn't discussed this, but the question of what the difference is between people is interesting.

@RAH, of course this is just speculation, but my guess is that they are currently very far from MTD. Based on the mice models they would have to double the current dose level to reach the same effective dose. And if systemic FAPa is significantly lower in humans than in mice (which it is) the MTD may be >3 or 4x the current dose level. How they make get to these levels in a reasonable amount of time is an open question. But increasing by just 40 mg/m2 each cohort means that P1a would go on for a few more years yet...which I assume is not feasible economically. So for me, the next dosing level is going to offer a good insight into where we are on the efficacy vs. toxicity curve.

The "1 out of 6" info is definitely a bit hidden. In the "Pharmacokinetics" section you will see an asterisk after the title of Figure A. If you then go to the end of the caption in Figure B of that section, you will see what the asterisk corresponds to, which is "Dox detected in 1 out of 6 patient tumor biopsies."

They've definitely done their best to downplay this key bit of info.

A good theory for the delay by Cellar Boy (https://twitter.com/boy_cellar/status/1618202824609005569)

"Delay is the FDA. With an application for breakthrough therapy, there needs to be a review of the clinical trial design and doses.

If I remember correctly, it's 60 days max for decision. Therefore avacta expects a decision by Science day."

That interview was from a while back, i.e., before they changed strategy to keep ava6k in house, and look to license out other candidates from the platform. This change happened last spring. Possible license deals would be:

1) ava3996, probably the highest value asset (after ava6k) since it will have undergone a year of pre-clinical trials.
2) license out the precision tech to another company that can add it to their existing on-patent chemo drugs (not sure if it would work with Keytruda or Trodelvy, but wouldn't that just be a cherry)
3) license out some precision candidates coming up after ava3996. These wouldn't be in pre-clinical studies yet, so i'm not sure if the value would be there to do that.

My guess is that these three are in order of likelihood.

Energy, great minds think alike! Reading through the 'breakthrough therapy' and 'accelerated approval' descriptions of the fda website (https://www.fda.gov/patients/learn-about-drug-and-device-approvals/fast-track-breakthrough-therapy-accelerated-approval-priority-review) it has ava6k written all over them. Avacta have proven that they're on the ball with their successful application for Orphan Drug Designation, so they must be looking into this, if not actively pursuing it.

In unbridled moments of optimism, I even wonder if this application may be the reason why the US sites haven't come online yet...although perhaps that may be pushing things too far.

Excellent post Wiggly! And beyond ava6k, the P1a results validate the mechanism of action for the rest of the precision pipeline. It's the same chemistry, which makes licensing deals that much more interesting. Each new drug will need to go through trials of course, and each will have some risk associated with it, but compared to typical pre-clinical drugs, much of the risk will already have been removed.

@5RINGS, yes that is exactly what happened, and at the time, the board was actually very clear on this point. They raised £45m with £10m going to diagnostics (part of which was used for the lft) and the remaining £35m went to therapeutics.
https://www.sharecast.com/news/aim-bulletin/avacta-raising-pound45m-to-fund-diagnostics-and-therapies-pipeline--7530827.html

Actually 5rings, the majority of the money raised back in the lft days was earmarked for therapeutics. That seems to have gone extremely well, wouldn't you say?

When last we heard from Sir Alan, last summer, it was fairly clear that P1a was expected to finish in the autumn, and that the results would be presented in detail at the Science Day. In fact, I always got the impression that the Science Day itself was being held as a good way to announce the results to the world.

Now, the situation is a bit more complicated. P1a won't be finished by Science Day. So the question is will they present everything they have to date, and try to make the same splash they were previously planning, or will they only present some of the results so far and wait for the big reveal next summer when P1a finishes.

What I had hoped for the big release was: 1) confirmation that it is activating (check), 2) confirmation that dox was found in, and concentrated in, the TME (check), 3) confirmation of little to no side effects (semi-check - yes they have said this, but i would like to see more detail and discussion on this, 4) that once in the tumor dox was behaving as expected (no check yet - yes it is obvious that it will, but it needs to be stated), 5) a few anecdotal stories about 5a) terminal patients that have made a remarkable recovery and 5b) anecdotal stories from patients about not losing hair and not feeling ill. Finally, I had hoped that they would discuss 6) possible licensing agreements and/or the next preCISION candidate to be brought into pre-clinical studies.

Now that things have changed, I wonder if the data release strategy has changed.

Depends if it is measured in the blood plasma or in the amount injected into the patient. If it is the former, then there will be no problem to continue dosing and no need to change the trial rules.