Member Info for Almostrich

Icecool, did you not read the bit where I said I have no experience around biochemistry and recommend DYOR. Haven’t claimed the post is error free.

As a consequence though, all of the the science in the post is that taken from the linked papers provided. No science input from me.

Glaring errors indeed! You could prove yourself a nice fella here though and contact the scientists who published the work and highlight the error of their ways!

Oh dear, I forgot your not a scientist are you.

Icecool posted 5 Apr 2023 12:43 “I’m not a scientist” Oooops!

Wonder why Avacta included that statement in slide 11.

It wasn’t put in as “filler material” was it?

Avacta wanted shareholders to read it. Why?

I guess AS just wanted someone from the audience to ask a question about it so he could do a bit of his infamous ramping.

Perhaps you could give us your interpretation. Second thoughts don’t bother.

Icecool if you’re still around come the next AGM I’ll be happy to introduce myself to you. I’m not AS as has been suggested you will be disappointed. And really I don’t think it’s me making you look bad.

I’m gonna miss the Grand Prix qualifying so I’m off

Oh dear you just don’t get it!

Plenty of different audiences here on Avacta LSE and I’m simply presenting some offerings to mine. Shareholders who are not LSE members that sit on the outside looking in not wanting to post (fear of ridicule perhaps!) only trying to keep themselves in touch with their investment by looking for sources of information, current thinking, reading whatever content serves their purpose.

Spend some time skimming the board regularly like this and you quickly create your own natural filter mechanisms, no need for those green boxes. Over time you develop an eye for the posts and posters that genuinely add value and knowledge to the board ( your’re not one I’am afraid, no offence) but generally one tends to focus on content rather than identities and motives.

All the one liners, put downs and other such crap; well utterly meaningless for this audience. I read and research, writing a post helps me consolidate my thinking, for a change I decided to post to the audience. That’s the audience that will have no interest in your posts! End result speaks for itself!

I’ll leave you with a quote:

"The whole problem with the world is that fools and fanatics are always so certain of themselves, and wiser people so full of doubts."

If only I were Doggy, sorry to disappoint. Serious amount invested here though. Science day/AGM great stuff so a sense of inner calm building. My research really helps me and I enjoy it.

Silly me though! I thought crossing swords with windy once only and an attempt at pulling down a deramper were the only rites of passage required to becoming o bona fide board member. The likes of Timster, Icecool, gje still working hard all hours as the board policeman, fine job lads!

Anyway, a massive shout out for gmcc, cracking job and I’ll continue to enjoy your output. Keep it coming! Thanks! Oh and BMN if you look in I truly owe you one. Your wise words kept me invested in the ups and downs of the lft saga. Truly thankful!

Not going anywhere, no way. Back to the stands for a bit of a breather! Next stop Dox, efficacy and sarcomas I think.

I’m away before the police come back. Cheers again!

I should also have said that hopefully even the doubting Thomas’s out there should be able to see that with preCision already in clinic trials and proven to be working (as a viable delivery mechanism) it maybe offers any potential pharma partners with this type of treatment in mind, a bit of a head start. A potentially less risky route through preclinical/clinic to approval. Again, if north else it will start conversations!

PT 2

I think this SMDC work first came to prominence in the world of Theronostics as OncoFAP appears on the radar of Sofie Pharma when talking FAP ligands for diagnostic use and is known to Point Bio and Novartis (via Clovis Oncology). A Swiss company called Philochem AG seem to be behind this work. Several other papers available charting its progress as a theronostic application.

Nothing to fear here for Avacta. Only the OncoFAP ligand part ie no payload has been administered to patients as a lutetium-177–labeled derivative for imaging studies which validated its targeting potential. At this point in time OncoFAP-Gly-Pro-MMAE has only been explored in preclinical models where it displayed excellent therapeutic performance.

https://www.philogen.com/philogen/wp-content/uploads/2022/10/20221014_Philogen_OncoFAP_Clinical_PR.pdf

Fascinating stuff this!

I get the impression that initially a large driving force behind the development of FAP targeting stemmed from theranostic activities. I came across a quote from 2020

“Thus, investors have recognized the potential clinical benefits and substantial financial upside of nuclear theranostics and are now in hot pursuit of the next relevant nuclear theranostics target. Fibroblast activation protein (FAP) has emerged as the front-runner, and the next gold rush appears to be around the corner.”

A few years on and we now have Sofie, Point and Novartis out there panning for gold!

I know this is all totally irrelevant to the current share price but it sure does emphasise that FAP targeting is being pushed forward, growing fast in different directions and with Avacta at the centre of its non-radiolabeled therapeutic use, ( and having started clinical trials), who knows what lies ahead?

Inevitably, as more published research like this circulates some light will spill over on to what Avacta are doing and the potential of preCision. I would expect these types of study to act as a catalyst, getting people talking at conferences etc and causing BP scientists and management to start knocking on a CEO’s door saying, “we need have some of this.”

Finally, a member of the audience at the AGM suggested that some investors are perhaps struggling with translation and communications around all this chemistry and oncology stuff. How right they are! Having a heck of a job trying to fully understand all the oncology language and science jargon surrounding AVA6000 making it quite difficult to grasp a full appreciation of the detail in the trial data etc. I’m trying to digest it but realise lack of expertise likely leads to a purely black and white picture when the reality is so much more likely to be several shades of grey.

For the record then, I have no experience around biochemistry etc My own interpretation tells me this is relevant to Avacta but make your must make your own mind up. As always DYOR!

This ostrich needs a glass of wine now!

Cheers!

PT 1

Final remarks after trawling through 2023 AGM slide presentation.

Bottom of the deck, p11, talking about the preCison Pipeline:

“Expand preCision pipeline with modern highly potent chemo toxins such as those used as warheads in drug conjugates”

Don’t think we’ve seen or heard a statement like this from Avacta before.

Thanks to Myles McN on Twitter who has already summarised the relevance below:

“Absolutely thrilled to read this!

Suggests that preCISION must be astonishingly specific to FAP, for avacta to be considering such therapeutics.

If AVCT can deliver the likes of MMAE to tumours without the need for a costly (and cumbersome) biologic (i.e. an antibody) - and with significantly reduced side effects compared to existing antibody-drug conjugates - then preCISION will indeed be in a position to displace the much touted 'magic-bullet' ADC.”

Again, I was intrigued so a bit more digging was in order.

Monomethyl auristatin E (MMAE) is a synthetic antineoplastic agent. Because of its toxicity, it cannot be used as a drug itself; instead, it is linked to a monoclonal antibody (MAB) which directs it to the cancer cells. Any alternatives?

PreCision technology is potentially a very safe way of delivering a deadly warhead such as a molecule like MMAE. Cool!

Then I came across the following:

https://pubmed.ncbi.nlm.nih.gov/36215129/

The paper has the title:

“Fibroblast Activation Protein Triggers Release of Drug Payload from Non-internalizing Small Molecule Drug Conjugates in Solid Tumors”

Unfortunately the above article is behind a paywall, so not much detail but it describes a new series of what are called Small Molecule Drug Conjugates, (SMDC’s) which are able to carry a drug payload to the TME where they are selectively cleaved by FAP. Sound familiar!

Specifically, the SMDC described here uses OncoFAP-Drug derivatives based on MMAE and dipeptide linkers. The authors have identified OncoFAP-Gly-Pro-MMAE as the best performing SMDC, which has now been prioritized for further clinical development and is the subject of the paper above.

Remember, AVA6000 consists of a doxorubicin molecule covalently bonded to a dipeptide (pyridine-4-carbonyl)-D-Ala-L-Pro), which is designed to be susceptible to hydrolysis by FAP.

Well in OncoFAP-Gly-Pro-MMAE we have the OncoFAP and -Gly-Pro molecule chain attached to the MMAE drug warhead.

Looks remarkably similar indeed to the preCision set-up as they are also using a dipeptide to link from a molecule, the -OncoFAP- to the drug warhead, MMAE.

You can compare the structures by finding OncoFAP-Gly-Pro-MMAE in Google images ( it only appeared a couple of days ago). The OncoFAP structure which delivers the drug payload is larger than the 5140 leaving group but we appear to be talking about an incredibly similar approach to the Avacta preCision mechanism referred to in the slide. It’s uncanny, I wonder whether Bachovchin/Tufts/Avacta’ s orig

“Result will be outstanding AVA6000 data package results that will encourage /confirm suitable partner interest in FAP - pre|CISION™ platform.”

Absolutely!

What intrigues me and has done all along is the emphasis from day 1 that P1a is going to be extremely “data rich.” Making such a statement at the outset made sense to boost the idea that there is more to it than a bog std P1a. At every opportunity AS et al have mentioned “rich” phase 1a data is important scientifically and commercially. They have a whole bundle of pk data plus biopsies. Anything else I wonder? Can’t help feeling there may be more under the bonnet here.

If the absorption, distribution and elimination processes after administration of AVA6000 are complex then surely some form of analysis involving data modelling and simulation would be applied to the clinical data to help understand and predict the behaviour of AVA6000 in humans. The clinical data tells them directly about AVA6000 and this will help guide dose and dosing regime selection no doubt but how much more can it tell them about the behaviour of the platform as a whole?

These days pharma have a wide range of extremely powerful computer modelling techniques available, mathematical, statistical, molecular which are not just applied at the molecular level (eg an AVA6000 molecule interaction with chemical groupings on FAP). There are software modelling techniques such as PK-PD, PBPK and others which are often used with both pre-clinical and trial data and have been used in Dox studies in the past, but they are all totally gobbledygook to me. No idea at all if they would prove useful in the context of this trial however claims that in recent years over 90% of companies that received new drug approvals by the FDA used this type of approach suggest there is at least a chance that Avacta may have such capabilities in-house or could access via a consultancy. Certara is one of many examples.

Publishing the full P1a data may provide the opportunity for potential partners to fully evaluate the platform by applying their own modelling techniques to the data if Avacta would allow it. In essence they would be able to further validate the AVA6000 data and maybe even make important judgements about the behaviour of the PreCision platform on a wider basis. Another step towards the licence/partnership agreements we’re looking forward to perhaps?

Yes, I could be a such a long way off the mark here but I do find it all very intriguing.

Advances in modelling capabilities could make early trial data a lot more valuable these days.

Bella, my guess is FAP has become a truly hot topic because of the opportunities it offers across so many areas of research. Theranostics, FAPI imaging and radioligand therapy, therapeutic studies, prodrugs for which Avacta are centre stage, immunotherapy approaches and others I’m sure. I get the impression there is broad potential in its diagnostic use alongside leveraging it therapeutically. All this is generating large interest and enthusiasm towards what might be achieved in the future which probably sustains many a conversation in the bars and restaurants after conference days at ASCO, AACR etc. Sure Avacta BoD and scientists will be talking about it to others, bet they can’t stop themselves!

Eliot Forster made some great comments in the Q&A starting at 57:08 when talking about tumours as being kinda funny things, as in peculiar not haha!

He made this point in reference to the TME

“ cancer cells in the middle and outside a thing called the stroma, it’s almost like a barricade that cancer cells build around themselves and those barricades are quite sophisticated and the really cool thing about our technology (and there ain’t many companies on the planet have this and lots saying we want it) is we hit the barricade and the actual cancer cells themselves both at the same time. That’s a very,very cool thing.”

He then went on to mention that there’s beginning to be a lot of excitement around FAP “because it allows us to hit the barricade. The one thing about modern cancer treatments is the barricade prevents them working and we’re going straight after it. So that’s cool”

Didn’t quite get what he meant, painting a picture that’s a bit more than the usual; level of FAP is higher or over expressed in the TME. Now I realise he’s saying FAP is in both the stroma and tumour cells in the TME. With the help of Google

“The tumor microenvironment is a dynamic composite of cells broadly categorized as multiple components of no-stroma and stroma cells, where tumor cells thrive”

Anyway the following research paper helped me a bit.

https://www.hindawi.com/journals/sarcoma/2023/2480493/#methods

In case the link fails the title is:

Fibroblast Activation Protein Expression in Sarcomas by Jacquelyn N. Crane et al.

Apparently the amount of work done to date looking at FAP expression in Sarcomas is limited with work cited being done over 10 years ago. How timely is it then that the above paper appears June 2023 prior to AVA6000 doing its targeting job on the FAP in STS patients.

The detail is largely too complicated for me but reading the conclusion tells us that sarcomas were among cancer types with the highest mean FAP expression by RNA sequencing. Also that the majority of sarcoma samples showed FAP expression by both stromal and tumor cells which reminded me of Eliot’s barricade description!

Interestingly the results also showed that FAP expression was found to be variable across the different bone and soft tissue tumor subtypes.

I’m sure Avacta would reinforce this statement:

“a more comprehensive understanding of FAP expression in sarcomas is critical to understand its potential utility as ……….a potential therapeutic target. This includes understanding expression of FAP by CAFs and tumor cells in the sarcoma microenviroment.”

What this highlights to me is the fact that Avacta are working at the very boundaries of current understanding despite how much is already known regarding Dox and FAP expression in solid tumours. FAP distribution so important, wish I knew what was behind the FAPI-PET imaging which appeared on slide at the 2022 AGM.

Ah well, time for this ostrich t

O&W if you’re interested plug the following into Google

Anthracycline-induced cardiotoxicity — are we about to clear this hurdle?

Wolfram C.M. Dempke

You should get an interesting paper top of list.