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Q3 in the Q&A - effectively "are you in contact with the FDA (and other regulatory bodies, and will you be going for Breakthrough Therapy Designation."

Answer: yes, we are in discussions with the FDA, and those discussions will be ***finalised*** in mid-2024.

What happens in mid-2024? The bi-weekly dosing arm ends, bringing an end to P1. The P2 trial design and tumour types will then be selected/finalised and it is at that time where Breakthrough Therapy/Accelerated Approval can be granted. Based on this, I would expect ava6k to be available on the market (at least in a limited extent) by the end of 2024.

Avacta have a working platform, opening up a pipeline of potential drugs, and the first of these (ava6k) is likely to get Breakthrough Therapy status. This adds considerable value to all the assets coming up behind, many of which would also qualify for BT status.

@AVCT - indeed, excellent stuff. And I guess it's not too much of a stretch to assume that Dr. Tap will be the treating oncologist in many cases.

Good question. I think simply that in a a P1a trial, you aren't allowed to dose patients who have a good chance to respond to existing therapies. This is why P1a trials are generally limited to recruiting late stage, likely terminal, patients.

@CJ - yes, I am sure that is true, that the clinicians will have been on the look out for patients for some time. However, such patients are (relatively) rare. Additionally, they may be actively recruited for multiple studies (and of course can only undergo one).

@AVCT - happy new year! That is what I thought as well (i.e., that the bi-weekly arm could include early stage patients as well). However, this was clarified by Estura (aka EmilyKate, aka maybe Mark? i can't remember) who asked this during the "Telegram Group meeting with AS and FMcL". He clarified that these would still be late stage patients, just those that hadn't undergone too much previous chemical treatments.

Hi CJ - screening just means that they are looking for patients for the trial. For some studies this can be quite simple and quick, while for others (like for the bi-weekly dosing arm of P1a) this may take some time. The reason is in the trial criteria. For this arm, Avacta are looking for patients that 1) are late stage (likely stage 4 and 5), 2) have had little or no previous therapy (i.e., no previous dox or other chemical treatments), 3) have high FAPa tumours and 4) are willing to take part in the study (i.e., forego traditional therapies). This is a tall order and so it is likely to take time to find the patients. Once patients are found, dosing can begin...they don't need to wait for a full cohort to begin (i.e., the patients are dosed as they come in).

As for why we haven't heard about the FDA approval, that was uncovered by our resident sleuth, Energyshares, who found that for trial changes, the FDA simply need to be informed and they have 28 days to respond to say if they don't want the changes to be implemented. i.e., there is no approval needed, just to inform them and wait if they say 'no'. If a 'no' doesn't come, then you can go ahead and start screening for patients.

Actually Feb. 6th.

@Aimhunter - yes, the Cmax reduction of >80% seems to be the main driver for the lowering of toxicities. However, the AUC reduction of 40-80% likely is a big benefit as well. How do we know this? If it was driven by AUC then we would expect that the MTD would only increase by a factor of ~2 between standard dox and ava6k. But since we are at ~3.5x and still no MTD, then it must be Cmax that is driving it.

Thanks Energy, great stuff, and I agree with you about 2024. As the kids are on screens with their new games, I also took the time to go over past presentations.

In the P1a results presentations from a couple weeks back, there were 3 things conspicuously absent:

-First, there were no cases from C6 (or C7). This is likely because the patients haven't been on the drug for enough time to show truly impressive results, but I have little doubt that they will in due time. So there should be some impressive case studies coming in the next weeks/months, especially considering the very high dose levels (and the fact that C7 patients may be first - or at least early - line patients).

-Second, there were no case studies from any non-STS patient (all 5 case studies were in various forms of STS). We learned in Sept. that they were seeing signs of efficacy in non-STS patients as well (in the RNS for the completion of C6), yet no mention of that here. Seems like a big thing to leave out. Yet, it fits with my view that the next big news will come for a joint venture (JV) with a big pharma company for ava6k for a (or multiple) non-STS indication(s).

-Third, there was no mention of cardiotoxicity. In the Sept. presentation this was mentioned, and highlighted in the interview. This seems like a major success and it's very surprising that it wasn't highlighted. Again, seems a key piece of information that they are holding close to their chest.

This was discussed a bit earlier this week. Estura told us that Avacta will not be presenting at JP Morgan. The AACR in early april is the next big chance to present the full P1a first arm results.

@gillbt - there is typically a 6 month wait from approval to first dose. and 2-3 month wait from submission to approval. so if they want to dose the first patient in 2024, submission must be relatively soon.

That’s my thinking too, PL.

My memory is that we were told early 2024. Neil Bell suggested back in early 2022 that the pre-clinical work would take "a bit over a year" which would have been March/April 2023, but this appears to have been pushed back a bit.

The pre-clinical studies should be nearing the end, with applications for an IND and US/UK clinical trials in the near future. Will Avacta start P1a for ava3996 on their own or will a partner be brought on board. While this drug is still 3+ years away from commercialisation, its potential market impact dwarfs that of ava6k, as it may be a "tumour agnostic" cancer treatment.

For me, it's up in the air whether we hear first about a license deal for a novel Precision drug or that the ava3996 trial is starting. Both should be early in the new year, in my opinion.

@NIgb

1) They were simply a group of investors who asked to meet with management. It had little or nothing to do with how many shares they owned or representative. Simply management communicating with share holders.

2) At any given time, there dozens of ongoing oncology trials at large hospitals like the Royal Marsden. The patients do sign confidentiality agreements and agree to not discuss their results. When the drug is given, it is not like it is a miracle cure, so that all staff (nurses, doctors, administators) would see this miracle result. It is only clear to the lead clinicians who actually know their history and see the CT scans for cancer progression, etc. And these lead clinicians are bound by professional ethics.

@BV - I think that this is explained on slide 13 in the Interim results presentation that we had in Sept (https://avacta.com/wp-content/uploads/2023/09/Avacta-Group-plc-Interim-Results-and-Business-Update-Sept-2023.pdf)

Precision is set, but there are two bits that can be added. A "capping group" and an "optional spacer" for "cleavage kinetics". The latter looks to allow the reaction to be tuned, to maximise when it is realised. I'm no chemist, but from this and what the company of told us, Precision is largely plug and play, with an additional dial to tune to maximise the results for any specific warhead.

Could be AVCT.

@WAG - I think it is important to separate two types of discussions. 1) would be for ava6k, either for other indications (breast, ovarian) or for certain geographies and the 2) would be to get Precision to attach a bespoke warhead.

For the first type, indeed clear efficacy signals are needed. Although the data just presented last week (covering C1-C6 and part of C7), assuming the full dataset is available to interested parties, likely already has enough info to make an informed choice. As has been stated, the earlier a partner comes in the cheaper it will be for them, although with a bit more risk. So they have their own risk/valuation calculations to do. If they wait until the end of the 2nd arm of P1a, and the efficacy for STS (and maybe other indications) is very clear, then the valuation goes up significantly.

For the 2nd type, it's not clear exactly how much more info the second arm of P1a will bring. Yes, it will be more patients with extensive data (always good) and likely more biopsies, but how important that will be for the Precision mechanism in general isn't clear to me. For this type of deal, the PK data that is already in hand should already be enough to have a very good idea of how much of the new warhead will be released in the tumour and the likely effectiveness of this concentration (based on their previous studies).

As BV has said a few times, for any company seriously interested in Precision, one would expect them to have synthesised the new Precision+warhead drug (or worked with Avacta to do it) and done preliminary pre-clinical tests (potentially already with mice - not a full study mind you, but enough to see if there is reason to go ahead with the deal).

Given the massive testing market at the time when those statements were made, they was perfectly reasonable. There was a massive market opportunity for a high quality, British made LFT. It was reasonable to assume that the UK government would actually fast track validation and support British industry, instead we now know that they held it back. There was also no way of knowing that a new variant would come along (at least not that quickly) that would be significantly less deadly which effectively collapsed the market.

I, for one, say that the statements made by the company throughout 2021 were justifiable at the time that they were made and don't hold it against AS or the BOD. But the danger in going after a highly volatile market like testing during a pandemic was the uncertainty in how long the market was going to last. And from everything I read about the mutations and spread of corona, reality was on the very short end of the distribution of probabilities predicted by the experts. Good for the world, bad for testing companies.

Here is a transcript of what Dr. Tap said at the science day about standard dox and what Dr. Coughlin said last week about ava6k. (thanks to BMH on X for posting the videos - https://twitter.com/BMHLTD/status/1736326494035603668).

Dr. Tap: "[For standard dox], most likely we don't see remissions, remission means that we see the tumour melting away. We can often see responses, but meaningful responses are only in 15-20% of patients. I'd love to see that increase. That can help with palliation, that can help with surgical conversion. But sarcoma is really a disease that we need to continue to treat. So having a drug that we can use for a long periods of time is what then translates into improved overall outcomes, like overall survival. And this also comes into the quality of life aspect where if you are giving a patient a drug that is not affecting their quality of life for the long term. That becomes really important."

"[For standard dox] median progression free survival (PFS) in a first line setting is 6 months and overall survival is 19 months and the overall response rate is 18%. I highlight this because sarcomas are diseases that don't always shrink when we treat them. So I don't always look at the RECIST response rate [how much tumours have shrunk], we look for stability, [stopping them from growing] and that's what is meaningful for patients. So we need to think about that when we interpret data. But I also want to point out the median number of cycles was just 4.2 months, which is hitting that limit of 6 [allowed] cycles. And median PFS is only just a few months after that. Why? Because when you stop the drug [dox] patients progress. That is one of the major limitations of doxorubicin, that we can only give it for 6 cycles."

Dr. Coughlin last week:

Dox is limited to 6 cycles (or 18 weeks, 4.5 months) and that is because of the cumulative toxicity. So the benefit that we have here with ava6k is not just that we are shrinking tumours but those tumours are shrinking and staying in that shrinkage, we're stabilising the disease for a prolonged period of time that just can't be achieved with dox. And that's right there with that favourable safety profile. So the patients have strong disease stabilisation, responses that last for time, and they are not experiencing the really problematic toxicities that are associated with dox."

It's almost as if Avacta have cracked it....

@oftinhope - indeed, especially for tumours like STS, the goal is to keep their growth in check. This was highlighted by Dr. Tap back in the science day presentation and by CC in the presentation last week. So instead of surviving for ~12 months (including 4-5 months of being terribly sick due to the chemo) when treated with standard dox, the patient may survive 24-36 months and have a much higher quality of life (low side effects). Also, for many patients, they can only have surgery if the tumours are below a certain size threshold. So shrinking them can be extremely beneficial.