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No, I believe it was to "carry out IND enabling studies", which effectively is to complete the pre-clinical studies, in order to apply to the various medical agencies to start clinical trials...which seems to be about ~6-8 months later.

Although, if the ava6k results are as good as we hope (i.e., matching or surpassing pre-clinical results) then I would assume that some fast-tracking could be done. Although this wouldn't apply to LG Chem trials.

For the ava3996 IND enabling studies, we were told that they are expected to take just over a year. That's the only reference point I have.

PL note the little winky smile at the end of that, indeed, uber rampastic suggestion.

Soft tissue sarcoma is a type of (rare) solid tumor, and metastatic just refers to the fact that the tumor has spread. So all this seems consistent.

Ah sorry, I thought it was being implied that ava6k could get ODD status for multiple conditions.

Indeed, there is nothing to stop ava3996 or any of the following drugs to apply for ODD status (other than if all the cancer types with potential ODD status are already targeted by Avacta ;)

My understanding is that no, you can only get ODD once per drug. I.e., you can only get the benefits once, so conducting trials on multiple 'low number' diseases wouldn't gain anything.

Thanks to Cellar boy on twitter for pointing this out. In June, Avacta announced their intention for FAPi PET imaging data in first quarter of 2023. I've always assumed that this will be a new PET imaging technique (as far as I can tell, FAPi PET imaging is still in development, with multiple versions being trialed), based on the Precision concept, i.e., bringing a tracing molecule into TME only using Precision.

If that is the case, then similar to ava3996, this is a massive hint that the Precision technology is working. You wouldn't start a new product/technique which is based on the same technology as ava6k, unless the technology was working.

I don't see it taking much time to put things together to present. 1) They already have the vast majority of the data in hand (including biopsies), so everything can already be put together and they can simply add data points later. 2) This isn't for a scientific publication, but an summary for investors. Qualitative statements like "few or no side effects", or "biopsies confirm activation in the tumour" will be fine (in fact, preferred).

If the data is as good as we hope/think, then I hope that Avacta PR are preparing slides and short videos to be shared with the media. No need to wait on any of this for the final cohort to complete.

Nope, I think it's always been two.

and thanks @gadgie for the link!

Thanks all, hopefully this was useful. Thanks to all for sharing your research, much better as a group effort!

@Lilarch, yes, I'm @jivetur88775834 (jive_turkey) there. I don't post much, more of a lurker.

(and the final...)

And during this year, they have undergone 3 dose escalations. I could imagine that they could increase the dose even if ava6k wasn't working (as long as the patients aren't showing any bad side effects). That's what the trial is for, so if ava6k wasn't activating, or not very much, at low doses, they may increase in case it does happen at a higher dose level. However, if it wasn't activating you wouldn't move on to Phase 1b, it would stop at the end of Phase 1a. The fact that Avacta are clearly taking it as a given that they will move on to Phase 1b is a strong indication...they are even saying which types of cancer they will be going for in P1b.

The only negative I've seen, is that the US sites haven't been announced yet. They may be online, and we just haven't been informed, or they were delayed for a multitude of reasons, or there just wasn't a need for them to get the patient numbers required. So there are many possible reasons for this, hence not a big concern.

Given the above, it is difficult not to conclude that 'it works'. And all indications point to it working very well indeed.

(continued)

May 11th, 2022 (RNS) - Therapeutics moves to London. My view is that if preCISION fails, the therapeutics division would effectively be terminated. Why? Because beyond preCISION, their focus is on TMAC, which is based on preCISION. While they are also looking at some affimer based therapeutics, this appears to be a minor portion. Hence, you would not undertake an expensive move and undergo a massive inconveinient move, if that division wasn't expected to have a long and bright future. As Neil Bell wrote in the RNS that the move results in "the increased potential to fast-track our innovative cancer therapies through to patients."

Winter/Spring 2022 - I don't remember when the first mention of biopsies was, but this has been mentioned in all subsequent presenations. Biopsies are expensive and a pain (i.e., approvals need to be gotten, timing after dosage, etc). There is no reason to get them, as a business in Avacta's position, other than to physically prove the mechanism of action and shout to the world "look at this, dox only in the tumour!". In the AGM presentation (June 2022), the biopsy results are explicitly part of the timeline going forward.

Spring 2022 - Avacta (through Linkedin), advertise a job for someone with experience with licensing deals in pharmaceuticals, specifically to work in the therapeutics division. While it is conceivable that this was unrelated to preCISION, I find that unlikely (I can no longer find the link for this).

June 23rd, 2022 - from the business update: "Focus on preCISION platform as the major near-term value driver". This seems pretty clear. Why raise investors expecations if you already knew it wasn't working.

June 26th, 2022 - At the AGM, AS states "...and we may not reach an MTD (maximum tolerated dose), wouldn't that be good". Equally, during the AGM, AS states ava6k "progressing very well". While this could, in principle mean that the trial is progressing well, AS would be very aware of how most would interpret this that ava6k is performing well. See also comments above in the Feb interview.

Sept. 5th, 2022 - ava6k receives Orphan Drug Designation from FDA. This would have been applied for on or after June 1st, 2022 (as the FDA have 90 days from application to approve/disapprove an application). These kinds of submissions take time and money. You wouldn't apply unless you were confident that it was worth it, i.e., why apply if you are just going to turn around in a couple months time and say "meh, it doesn't work as well as we hoped." I thought that this would be spark that wakes up the market...but was clearly wrong.

As for safety and tolerability, I think we can be very confident on this front. As the doses escalations keep increasing significantly, and Neil Bell wrote that the second escalation "is an endorsement of the emerging safety and tolerability profile" (from that RNS).

(continued)

Feb 7, 2022 (Vox interview) - AS states (3:50) "..it is the oncology drug development that really drives the value of the business....despite the dissappointment of antigen testing [for covid], fortunately the big value driver is really motoring along extremely well." If the data weren't looking very good at this stage, a comment like this would be nothing short of a bare faced lie.

Same interview (11:30), we heard (AS and FMcL) that they are "very happy with the data, it's very consistent" and that they are "very happy with what they have seen so far". Wow.

March 21st, 2022 (RNS) - appointment of Christina Coughlin as a non-executive director. I find it difficult to judge exactly how 'world leading' she is, although she does clearly have a lot of experience. To me, the main take away is that there would be no reason to appoint an oncologist onto the board, if you weren't expecting your oncology platform to be a large part of your business going forward.

March 29th, 2022 (RNS) - release and subsequent discussion of some of the pre-clinical results for ava6k. This was designed to bring significant attention to the platform and Avacta in general. Needless to say, the data are amazing. In the worst case scenario and ava6k wasn't working, these results were released to justify Avacta's decision to run the trial in the first place, i.e., if the results were bad they could tell investers; "look, we had every reason to be positive and excited, but it just didn't work out". But, if negative, why would you do this on the world stage, instead of just releasing them in some journal and pointing investers there? By presenting at the AACR, that is screaming to be noticed. Also we learned that they used *human* cancer cells transplanted into mice. So we know that ava6k was activated in human tumors in the pre-clinical studies. That removes huge uncertainties and explains Avacta's confidence going into the trial.

April 2022 (AS layman's presentation of pre-clinical results) - "...and it is this specificity that has allow us to succeed where others have failed." It's true he was referring to the pre-clinical studies but it would take some serious cynicism to present and say this, knowing that it wasn't a success in humans.

April 6th, 2022 (Business update presentation) - AS "We can be guided by those PDX models which is why we are so excited that this is a very significant improvement in therapeutic index." AS also stated, in the questions that FAPa levels are much higher in rodents than in humans. Pretty amazing thing to say.

This post is meant to be similar to the famous "Why" post by Energyshares a few months back, but a bit more flushed out, and with references. Sorry for the length, but looking back, it's pretty amazing how much info we have been given (especially when one reflects on the current stock price).

Avacta have kept their cards close to their chest regarding whether 'it works'. For it to 'work', two criteria need to be met: 1) it activates/cleaves in the tumor microenvironmnet - TME, and 2) and that it is safe/tolerable. If those two are satisfied, we know it works, as dox is well known and understood so its effectiveness isn't in doubt. While they have been quiet, that's not to say that they haven't given clues, or even told us in advance what the steps would be and what success would look like. Here is my bull case:

Aug 11, 2021 (RNS) - First patient dosed

Neil Bell (Aug. 19, 2021 interview - 14:05) - states that Avacta have their own monitors that go in to the sites (i.e., hospitals) to check "all the data". So along with the safety committee, Avacta are keeping a close eye on the data in real time. This is key, Avacta know how things are progressing.

Alistair Smith (AS - CEO - Feb 25th, 2021 Vox interview) - states "The key timepoint will be before the end of the year [meaning 2021], we will see the first PK data. And that will tell us whether the precision platform is activating the drug in the tumor predominantly...and that is enormously important as that tells us if that precision chemistry is working in human and we can translate that into a whole pipeline of other chemotherapies that we have waiting."

Neil Bell (before the trial started) - confirms that they will select the next candidate for pre-clincial (IND enabling) studies once the 'mechanism of action' is confirmed for ava6k (https://twitter.com/tom_the_bomb__/status/1546477019088691200).

Nov 21, 2021 - FDA IND approval. Would have been applied for ~30 days previously, and the application must include any results from previous clinical trials (plus pre-clinical of course). At the time of submission, cohort 1 patient 1 (C1P1) would have been dosed multiple times and C1P2 (and possibly C1P3) would have already been dosed, so that data must have been included.

Second half of 2021 (taken from the June 2022 AGM presentations) - "Multiple appointments to the Therapeutics Scientific Advisory Board". You would not waste time and money bringing people in if you weren't going to need their advice/experience. So a good indications that things are going well with the trial.

Jan. 18th, 2022 (RNS) - second preCISION pro-drug candidate selected (ava3996) to begin preclinical IND-enabling studies. Neil Bell told us this would only happen once 'mechanism of action' is confirmed with ava6k (see above). These studies cost a lot of time and effort. You simply wouldn't go down this road unless you had a lot of confidence that this drug (and the platform) is effective

Yes, that's true. Everyone in a single cohort gets the same dose level. So if you start at 80, you'll stay at 80 until either you start showing unacceptable side effects (i.e., a cumulative MTD is reached) or some think, the cumulative MTD of standard dox is reached.

I find it hard to imagine that Avacta would keep drawing attention to the trial if it wasn't working. Surely, they would push it to the background so as to not create false expectations and also bring more scrutiny when they would have to eventually disclose that it wasn't working. Definitely a positive sign.

@MrA, simply that MTD lies outside the tested range.

@Energy, I don't think that checks out. Why would the same patient be given a single dose at each of escalation steps? In a trial, a patient can only belong to a single cohort. If a patient in the first cohort was still in the study, they would have been receiving 80 mg/m2 every 3 weeks for 410 days or ~19 doses. Which would mean a cumulative dose of 1560 mg/m2 or ~1050 mg/m2 dox equivalent. So much much higher. The question is whether they can dose over the normal limit and whether a patient would continue this long...although with minimal side effects, I don't see why not if they see that it is being effective.

I agree RAH, the clinical data must be included in the submission and at the time of submission Avacta knew whether it was activating. Hence, it must be looking good, especially with STS.

I think that the problem with the market comes from this quote from AS in the RNS: "We are delighted to receive Orphan Drug Designation from the FDA for AVA6000, which is a reflection of the high quality of the preclinical data and the potential benefit the pre|CISION platform can bring to cancer patients."

People have focussed is on the "pre-clincal" and "potential benefit", which has overshadowed this amazing news.