Roundtable Discussion; The Future of Mineral Sands. Watch the video here.
@54 - where was that in the book? I must have overlooked that, but is sounds amazing. Thanks.
@AVCT - good question, I don't know. One of the problems with ADCs is that they do have a lot of off-site cleavage, so it could be related to that, although you're point stands, that doesn't seem like it should be enough. But if there is little or no HER2, i don't see how the ADC would make it into the cell.
And you're right about the stroma and EF. It's just good to get a totally independent take on its importance.
@AVCT - that is my summary from the two paragraphs I posted. The Enhertu results showed that even when cells didn't have much of the HER2 protein (which is the protein on the surface that is targeted by the ADC), there was still some cell killing going on (which due to the "bystander effect" is good). So the implication is that the ADC didn't make it into the tumour cells, because there wasn't the HER2 protein to bring them in.
The bystander effect. This is a clip from an article on ADCs posted on X today by Antonyblood1 from the JapanTimes.
"A real turning point came in mid-2022, when AstraZeneca and Daiichi Sankyo showed that their drug, Enhertu, extended the lives of women with advanced breast cancer by six months compared with conventional chemotherapy. Moreover, the drug was being tested in women whose breast cancers had low, at times barely detectable levels of HER2, the protein that the drug homes in on before releasing its chemo. That suggested some of its power comes not only from its ability to kill cells expressing HER2, but the chemo’s ability to take out neighboring tumor cells, too.
This bystander killing seems to be an important component of good activity, said John Lambert, who consults for a number of companies on antibody-drug conjugates and previously was the chief scientific officer at ImmunoGen. And exploiting it could really open up the field for these drugs."
Summary: ADCs are better when they release (some of) their warhead in the tumour micro environment.
From Q&A Q7 today about Precision: "By targeting release of the payload in the tumour microenvironment, there will be a bystander effect i.e. all cells within the vicinity of the payload will be killed."
Boom.
Q7 and Q8 are very insightful. ADCs (antibody drug conjugates) are the bee's knees these days in cancer research, i.e., companies are scrambling to buy/develop new ADCs, with over $20B in deals this year alone. The ADC market is currently ~$10B per year and is expected to grow to $20B-$34B by 2028, depending on the forecasts.
Precision is a direct competitor to ADCs. Both are doing effectively the same general thing, bringing the 'warhead' directly to the tumour in order to spare the healthy tissue. Offsite toxicity for ADCs remains a serious problem, i.e., healthy tissue is often targeted as well, so the specificity has been a real problem. Following on Avacta's response, it seems that the ADC is designed for the antibody (mAB) to be linked with a warhead, and the antibody is developed so that it attaches to a specific antigen (a protein) on the cell of a tumour. The whole ADC is then needed to be brought into the cell. This is the key, because most antigens aren't able to bring the whole ADC into the cell, i.e., being attached to the surface doesn't help you, it needs to be brought inside the cell. Only once inside the cell does the warhead get cleaved from the anti-body (in the lysosome) which can then go on to kill the tumour cell. Effectively, the 'cleaving' happens inside the cells.
Precision, on the other hand, doesn't need to be brought inside the cell. Ava6k gets cleaved by FAPa which is on the surface of the cells (both tumour cells and stromal cells). Once cleaved, dox can permeate cells by itself, so it gets inside not only the specific tumour cells but also the surrounding stromal cells. This is was Elliot Forster was saying at the AGM, Precision doesn't just hit the tumour cells it also hits/kills the surrounding stromal cells, which often act as a barrier to protect the tumour.
ADCs are complex and expensive to make, and even more expensive to develop. Precision is relatively straight forward and inexpensive to make. The details of the mechanism of action also make Precision potentially more effective. If the data continue to be as good as we've seen, I see little reason why Precision wouldn't go on to displace much/most of the ADCs market.
Given the complexity and the amount of money and resources put into developing ADCs it seems amazing that something as elegant and simple as Precision could come along and solve the problem in a much more straightforward way. But the specificity and selectivity was lacking in previous attempts, too easy to cleave the warheads so too much offsite delivery. But Precision solves this, only cleaved by FAPa and not by the myriad of similar enzymes around the body. A pretty amazing discovery by Prof. Bachovchin and team.
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.