Member Info for jive_turkey

I would expect C7 to finish by the end of Feb (in fact, it could reasonably finish any day now). However, I wouldn't expect any data until a full presentation, hopefully at the AACR in April. The told us in the Q&A that they held back some data from the Dec. presentation to present at upcoming conferences, and I would assume that the C7 data would be part of this.

Hi Energy, I think ODD status has been largely overlooked, and totally discounted by AIM. This is a major accomplishment, and as stated by Avacta during the Q&A they are currently in discussions with the FDA. The discussions are almost certainly about 1) the design and implementation of P1a arm 2 and P2 and 2) the requirements for accelerated approval. My belief is that we will see limited approval already next summer at the end of P1a.

As for the bi-weekly dosing, I don't think that was an FDA suggestion. It is long known that dox has a much higher efficacy with more rapid dosing, something that traditionally simply can't be done due to the side effects of dox on healthy tissue. Remove those side effects, and a weekly or bi-weekly dosing regimen becomes the obvious choice, hence targeted by Avacta from the beginning.

My prediction for the next RNS is the 1st patient dosed in P1a arm 2, followed relatively quickly by a license deal, i.e., allowing another company to use Precision to put their chemical warhead (an MMAE?) on.

Hi Bella, I don't think so. First, early funding rounds for startups (like AffyXell) are often kept closed, so the amount of funding raised is not publicly released. Second, ava6k is not a cell therapy. Cell therapy refers to placing new healthy cells in the body (i.e. though Mesenchymal stem cells - something that Daewoong are experts in) or altering the immune response. ava6k does neither.

Third, AffyXell focusses on stem cells and the immuno-response of the body to immune diseases and transplants (i.e., host vs. graft disease). It has little or nothing to do with cancer therapies. So it would be odd, to say the least, to pivot to an entirely different therapeutic space.

Finally, GenScript ProBio is all about facilitating drug and treatment discovery and development. That fits perfectly with AffyXell and its therapies. ava6k has already been developed and so what we need is a big player to pay for further clinical studies as well as the manufacture ava6k for distribution. GenScript doesn't really fit the mold for either need.

I think AffyXell's mission and focus are pretty clear, combining Daewoong's and Avacta's expertise to make a big splash in immune diseases and graft-vs-host disease. Moving into oncology doesn't seem likely.

@DTW - good summary.

@CTSFO - thanks, glad it was helpful.

@Blackcat - I think that map of the current ADC space is excellent. A couple things to note though. Avacta's affimer programmes (i.e., ava028) are not competing against ADCs. Instead, they are immunotherapy therapeutics. So they don't bring a warhead to the tumour, rather they help our body's immune response attack the tumour. It would be interesting to see/hear if an ADC with an affimer rather than an antibody would improve results for ADCs. So Avacta's products (at least those that are currently in the pipeline) will never appear in the ADC map. Precision products could, but of course they don't use antibodies or affimers.

What the ADC map does do however, is show in graphical form, just how exciting ADCs are at the current time. Nearly every large pharma company has placed a significant bet on ADCs, and the expectation is that the market is going to grow exponentially over the coming years. After reading in more detail about ADCs, their inherent complexity (both in how they operate and in how they are produced) is clearly a strongly limiting factor. This is what gets me excited, Precision is simple and powerful, and offers tremendous advantages over ADCs. This is clearly a disruptive technology in a field worth tens of billions of dollars per year.

Check out this (fairly technical review article on ADCs) if you want more details on the above: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10464553/

As has been recently discussed, Precision and ADCs (antibody drug conjugates) are attempting to solve the same problem, namely bringing toxic warheads directly to tumours, thus sparing healthy tissues. ADCs are made up of an antibody (which is going to attach to an antigen on the surface of a tumour cell), a linker, and a toxic warhead (i.e., a chemical that is going to do the cell killing once it gets inside the cell). ADCs are all the rage in oncology these days, with billions spent in 2023 on pre-clinical and clinical ADCs. In the recent Q&A, there is an excellent overview of the benefit of Precision over ADCs.

Which got me thinking, has doxorubicin been used in an ADC? The answer is yes. Once of the first/second generation ADCs used dox (Immunomedics - IMMU-110) and made it to Phase 1/2 trials. This was eventually dropped because of a lack of efficacy. Effectively, what happened is that not enough dox was getting into the tumour cells, so it wasn't effective. This was largely true of all the 'traditional chemotherapies'. They just are not toxic enough. So right there, you see a major win for Precision...it is able to bring enough dox into the TME to have a significant clinical response at reasonable dosing levels.

In order to overcome this, more toxic payloads were developed, being 3-5 orders of magnitude more cytotoxic than dox (dox is one of the most toxic of the traditional chemos). This means that these new ADCs can have more anti-tumour effects, but it also means that there is more offsite (i.e., non-tumour/healthy tissue) damage. Unsurprisingly, the result is that most of the ADCs that have been tried with these new warheads have too much toxicity, causing terrible side effects, as even a little offsite delivery will cause serious damage. An example of this, is two drugs using the same antibody, but with different warheads. Enhertu (one of the most popular approved ADC) has a much less toxic warhead than two ADCs in development (which use the same antibody), but the two more powerful warheads were taken out of clinic due to serious side effects.

The take away is that ADCs need extremely toxic warheads in order to get a response in the tumour, but that this generally causes a lot of problems in healthy tissue. So it is a fine balancing act. Precision (ava6k) works with traditional chemotherapies, as it is able to bring enough of the drug to the tumours for anti-tumour effects. It will be interesting to see what happens with Precision when even more toxic warheads (MMAEs - 3-5 orders of magnitude more toxic than dox) are used.

And to repeat from the Q&A and other posts, ADCs need to be internalised by a cell in order to kill it. This is what it is designed to do, bond to the surface of a cell and then be brought inside. Precision is cleaved outside the cell, and the warhead can pass through the cell membrane by itself, giving a 'bystander effect', killing nearby cells too, i.e., in the stroma. A big adv

I've been a bit confused on this. Is ava032 the same (or another version) of ava028? Both are PD-L1 inhibitors. ava028 appears in the pipeline, while ava032 appears in the presentations...?

@CTSFO - the Boston conference was a relatively small one, and Avacta only presented two posters, with research level results (i.e., even before pre-clinical). JPMHCC is for big announcements and company results. This would have matched for full ava6k results, but it appears that it was just a bit too early for a full presentation.

@alex - no, he will present his team’s research, not clinical trial results that he is taking part in. Clinical trial results belong to the trial sponsors (ie Avacta).

@LDA- a meeting (however positive) with the FDA is unlikely to be RNS worthy. Submission or acceptance of an IND application will be when we next hear something on this.

$66m upfront payment for a pre-clinical programme.

I find the focus on 'hurdles' from the article quite odd. Imagine having a product (a weight loss drug in this case) where the market is more than an order magnitude larger than what you can provide at the moment. Which means every little bit that they can provide will be bought, and that is likely to continue for years to come. Yes, there will be competition, but they will sell every ounce they make for years. The only question is should Novo Nordisk build another 5 factories or another 10?

Yeah, the UK pays less per dose than other countries. That is the benefit of mass negotiation. So what? Other countries pay more and Novo Nordisk's bank account grows faster than nearly any company in the history of the world.

Hurdles? A poison chalice? A very strange perspective.

And of that $100m upfront payment, $20m is in the form of new shares being issued by the company. IMO this could be a good option for a deal with Avacta, dual listing on Nasdaq with some fraction of the upfront payment in these shares. Kill two birds with one stone.

Because there are 1000s of companies that one can invest in, and one needs to research in depth to find out where the value lies. Why didn't everyone invest in Apple in 2005? Or amazon in 2008 or Moderna in 2019? At the moment (despite the passionate base following), Avacta are a small cap, effectively unknown, British biotech. We're lucky to have this opportunity, stumbling a company with this potential.

I, for one, have told a number of people about Avacta, and once looking into it, nearly all have invested heavily. They simply had never heard of Avacta before.

Nevermind, found it. Great stuff!

@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.