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I'm suspicious why we do not yet have a new CFO.

The CFO announcement may be delayed because it is to be made public - (or pubic even, as I just mis-spelled it),

co-incident with another announcement about a deal of some sort with the new CFO's current employer.

(CC mentioned 'he's American').

That sort of arrangement is not new to me, and may repeat here - I'm not sure, but nothing more than a possibility.

While it is sort of a smear there's high low, we can actually create an understanding of tumor types where there are FAP low populations, so the more heterogeneous diseases. This is where we really think that this mechanism, the FAP Affimer drug conjugate, will have an important role to play. It's Going to essentially slow the drug down within the tumor and allow the low level of FAP that fighting chance to cleave the drug. We think this is going to open up a number of different diseases where we don't see that extremely high level, those more heterogeneous expression patterns of FAP, so opening up a whole new avenue of solid tumor indications for us.

Q thank you for this Chris, it seems like Avacta definitely have some promising milestones on the horizon. Finally what in particular excites you about where Avacta will be in the next 12 months?

A I think there are two things really. The first is you know FAP enabled therapies. This is a target that you know in the oncology field we've been looking at for quite a long time. We've looked at small molecules, bi-specifics, ADC's. There’ve been multiple approaches. Not all of them have had efficacy, and I get asked a lot ‘what is the difference about the effect of approach. What is the difference with preCISION’. Targeting the Stroma here the tumor micro environment, it isn’t as straightforward as targeting tumor cells. However, the approaches like preCISION that leverage the bystander effect. Not only are we directing the therapy to the tumor, to the tumor micro environment, to the stroma, but we're actually leveraging the bystander effect. The bystander effect meaning that that therapeutic drug, the radio ligand, it's going to be able to attack the tumor cells and not just the Stroma. That's where I really think we're going to see a gain in these approaches of targeting the Stroma, targeting the tumor micro environment. That's what's so different about the Avacta approach. I mentioned radiotherapeutics. It’s another approach that has been used with FAP, and it has seen some nice activity, but again it's back to that bystander effect, and we're perfecting that right now, at Avacta. I'm most excited about preCISION. We've got 10 years left on our foundational IP. We've got 10 more years to make improvements in this generating new IP, generating new know-how. We have found as we just reported at science day and in Barcelona at the triple meeting we've got new approaches to different warheads. We're now able to attach even more potent warheads. That's the gains that we've seen with our exatecan program. New options. You know, what I'll say is stay tuned. Avacta is really just getting started.

And to be honest with you, the other way to do this if we don't leverage that AI database, is an empiric look at multiple different tumors within the phase 1. That takes a long time and it takes a lot of patients to be treated in a phase one. We've seen that a bit with AVA6000. We looked across a number of different disease settings, not all of them were ‘sensitive’ to the mechanism with the high degree of FAP. What we're really excited about in Tempus is to accelerate our drug development of AVA6103, and enter the clinic with a high probability of success in a small subset of tumor types, where it would be sort of the best guess that these would be the tumor types that would be the most sensitive. Again informed by that Tempus collaboration.

Q The second new preclinical asset is AVA7100 creating a new type of therapeutic called an Affimer drug conjugate could you tell us more about this?

A The Affimer - Let's break this one down as well. The Affimer has a few advantage over an antibody. It is based on a human protein so Stefan A is the scaffold. It's much smaller than an antibody. We don't need to make an acceptable drug conjugate. We don't need all the Bells and whistles in the large molecule of the antibody. We get that we want the binding domains, and we want places where we can attach our drug. So the Affimer was the best of all Worlds in that we could insert the binding domains. It's very small compared to an antibody. Even an Affimer dimer is still a fifth of the size of an Antibody, so will easily fix that tumor penetration issue. Our scientists have been able to engineer into that molecule four different cysteines. So with that we can now leverage the sort of highly site specific conjugation methods that have been developed in the ADC field. And we’ve also developed the chemistry of our peptide, our preCISION peptide, in that we are now able to attach one end of the peptide to the Affimer through that cysteine maleimide conjugation, and the other end can be attached to the warhead. Now we can take that preCISION peptide, essentially use it as the Linker in the ADC or in the AffimerDC, (the AffDC as we call them here). We've chosen with our first program a FAP directed or a FAP binder Affimer drug conjugate for a couple of reasons. The first is that we think the Affimer with binding affinity’s that are very similar to antibodies, - even more potent than antibodies in some of our iterations, - but we can now attach the Affimer drug conjugate to FAP on the cell, and the FAP adjacent to it, or the FAP on a neighbouring cell, can now cleave the peptide drug conjugate, and now release the warhead. Where we think this is going to be a really important mechanism is going to be in FAP low tumors. In the last question where we talked about our Tempus project, one of the things that we're excited about is that Tempus can use different cut points, and use different ways of slicing and dicing and looking at the expression.

What is that dose that we're going to want to use in patients. The third aspect is that as we get both of those the manufacturing the toxicology and the pharmacology ready, we're now prepping for our conversations coming up with the health authorities. A common thought or a common misconception is that we just submit to the agencies. Not true. We can actually have conversations, the FDA has an entire program called the pre-IND where we can have conversation before. It allows us to do an early presentation of mechanism of action the pharmacology the early days of toxicology and we give them a draft of the trial, and we have a collaborative conversation about this. All of these aspects, those three that I mentioned can take but before hitting go on manufacturing and really being ready to file that IND. Again we work collaboratively with the health authorities on approving and then opening the trial in the US similarly we will work with MHRA to open the trial in the UK. It is important to note though that these agencies are independent, they can have different timelines, and so we will get going as soon as we can but looking forward to the next chapter the IND enabling studies for AVA6103.

Q Thank you. you briefly mentioned Topo isomerase 1 inhibitors, so when AVA6103 does eventually reach the clinic which cancers could it be used in.

A That's a great question so you know there are hints that we can take from the clinical development of a number of Topo Isomerase 1 inhibitors. There are some that are on the market topo tecan, Ireno tecan, these are much less potent than exatecan, but are used pretty frequently in clinical oncology. If you take a look at FAP expression and take a look at Topo Isomerase 1 sensitivity, there's a large number of diseases that we can think about. This is really where we're going to see the benefit of our collaboration with Tempus. In this project that we've just recently announced and recently kicked off, together with the data scientists and the statisticians at Tempus, we are accessing their lens platform. This is a database that includes data from over 200,000 patients that have been treated. It has over 7 million data points. So it's not just information about the tumor, expression in the tumor, there's clinical data, there is a wealth of information in this database. What this is allowing us to do is look collaboratively and very quickly using their AI engines, at genes that are predicted to be sensitive for tumors that are sensitive to Topo Isomerase 1. But also it allows us to compare, within that database, the FAP expression. And so using this AI tool, and this tremendous wealth of data that we have within Tempus, it's going to allow us then to take a look across all of these disease settings, spit out where are those diseases where we would predict Topo Isomerase 1 sensitivity, and FAP overexpression.

It has been in patients through a number of phase 2 trials, and so we know the safety profile and we know that there is a tremendous amount that we can do to improve it. The second reason is a cousin let’s say of exatecan, durexatecan, has been a highly successful ADC warhead. And so we know that there are several tumor types quite sensitive to this, but again they're limited by their targeting modality. So let's talk about in her two highly Potent Top Isomerase 1 limited by her two expression fap is a bit broader and is going to allow us to move this into a number of different diseases. I mentioned there's three the third one exatecan can failed in the clinic for two reasons and preCISION can fix both of them. The first is that it has very challenging therapeutic index. we've mentioned about half of the patients that receive standard dose doxorubicin have severe neutropenia. Doses that were effective with exatecan, 90% of patients with severe neutropenia. so a very challenging therapeutic index. But the second problem is that it has a PK liability. It only has a half-life when it's infused through the veins of nine hours doxorubicin is 35, so we're going to have to fix that. So the key point here with the chemistry gains that we've made, preCISION can now create a sustained release mechanism. that's how we can now direct the therapy into the tumor sustained release in parallel keeping it out of the bloodstream. We can fix both of those problems with exatecan. Gains in the peptide and important parts of the peptide and we've now done a really careful look at what that next warhead that we want to look at, so we're excited about 6103 moving into the clinic.

Q AVA6103 is currently in preclinical IND enabling studies. Could you tell us a little more about the future plans for this asset?

A What this stage of development represents is that there are essentially three things that we do in the next stage for AVA6103. The first is we have to get ready for the clinical trial in terms of manufacturing. So the way that we make it for the preclinical studies is very different than the way that we have to make it according to good manufacturing practices for the clinic. That can take some time to get it right, and so those studies have just kicked off or AVA6103. The second is we now move to more intense pharmacology but also it get started on another aspect before the clinical trial which is the toxicology. And understanding really predicting using different models. What are the doses that we're going to be using in patients. We have the trials with exatecan to guide us, and so understanding where we are in terms of the toxicity the MTD the maximum tolerated dose that is observed across species is going to be critically important for us to predict.

Transcript of this interview follows.

I found what she has to say about the use of the Tempus 'Lens' database, and the speed with which project progress increases, really good news. The faster we can progress AVA6103 the better, as more and more patents can be expected to be registered, increasing the value of the company sooner, and useful when we get to discussing T/O negotiations.

Peel Hunt ‘Expanding the Pipeline’ Interview with Avacta CEO Christins Coughlin 27.11.2024

https://peelhunthealthcarelifesciences.gallery.video/241127

Q Avacta has been very busy since we last spoke about the phase 1 data from AVA6000. With two new novel pre-clinical assets recently announced. Firstly we have AVA6103, could you give us a brief overview of this therapy deck.

A Lets take our preCISION medicine apart and take a look at the different components. We talk about these as peptide drug conjugates. The peptide is the key part. We refer to it as a micro peptide, it's only two amino acids and a chemistry cap that's attached. That micro peptide is actually attached then to an active anti-cancer drug. There's three key points to mention about this preCISION peptide, that we used to mask the drugs within the bloodstream so that they're not visible to normal cells. The first is our peptide binds to FAP in the tumor micro environment, it's then cleaved by FAP in the tumor microenvironment. These two together lead to the release of the active drug right there in the tumor, where it's supposed to be. Importantly that peptide once it's released isn't visible to the immune system. I mentioned it's a micro peptide it's only two amino acids, and so it's too small to be an epitope, it's too small to be considered by the immune system to be a foreign protein. Other ADC’s, other peptide drug conjugates, these peptides that are larger, would be subject to these. Not true with preCISION. We avoid a series of key toxicities, the immune-based toxicities with this peptide. Now I mentioned it's a mask. The peptide that we attached to the drug now prevents that drug from entering normal cells, so it's going to prevent the toxicities and again release the drug right in the tumor micro environment. The second part of the new molecule AVA6103, is the active drug we've chosen exatecan. Why? AVA6000 as you mentioned, we've seen some nice activity in the clinic we've learned a lot about preCISION through that clinical trial. We've seen that with AVA6000, it's key that the tumor types that we're targeting are sensitive to the drug so sensitivity to doxorubicin is critically important for us. We're also looking for settings with high unmet needs, settings with FAP over-expression and Topo isomerase 1 inhibition is a key mechanism of action right now in oncology so exit can with a good choice for us for three reasons first exatecan is about the most potential one inhibitor out there.

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