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Folks on X getting excited! AVA6000 destroying the stroma?

Thanks to Marty McFly & Cumulus.

“I believe that Avacta is protecting IP having evidence that preCISION is breaking down the tumour stroma, permitting access to the tumour.”

“Increasingly it seems to me that the strategy of targeting the Tumour Micro Environment, rather than cancer cells, with next generation conjugate drugs might just be an idea whose time has come.”

Hold on a minute! The idea that AVA6000 is destroying the stroma. I’ve read about that type of behaviour before!

It’s very interesting that way back in 2012 these guys published a study that validated the proteolytic activity of FAP as a target for the activation of a systemically delivered cytotoxic prodrug and demonstrated that targeted killing of cells within the STROMAL compartment of the tumor microenvironment can produce a therapeutic response.

https://academic.oup.com/jnci/article/104/17/1320/896574

OK, I know doxorubicin is different to the thapsigargin cytotoxic agent used in this study but I believe dox also induces apoptosis so the discussion is likely to be very relevant indeed regarding possible AVA6000 dox mechanisms.

What makes me laugh is the fact that the fudsters believe BP had no interest in Bachovchin/Tufts peptide chemistry because of a belief it wouldn’t work. Whereas the truth probably lies closer to the fact that BP couldn’t spot the potential. Clearly the work of Brennan 2009-2014 added to the conviction that Avacta must of had that Arisaph ARI-3099DOX would prove to be a successful prodrug as AVA6000.

See part 2

Improved safety! Sometimes we need to see the numbers to really understand and appreciate the size of the problem and the potential impact AVA6000 will have on improving patient safety alone.

“lack of the significant cardiac toxicity that is often seen with doxorubicin treatment.”

Professor Chris Twelves, Lead Investigator and Professor of Medicine, University of Leeds, commented:

“The AVA6000 data presented at ESMO continue to demonstrate encouraging efficacy with several ongoing, durable responses.The observed efficacy aligns with a highly favorable safety profile including a lack of the significant cardiac toxicity that is often seen with doxorubicin treatment. 

Here’s what he’s talking about

In the period from January 2004 to June 2022 One hundred thousand and seventy‐five AE reports were obtained for doxorubicin (ADM), epirubicin (EPI), and liposome doxorubicin (L‐ADM) from the FDA adverse event reporting system (FAERS database). Cardiac failure, cardiotoxicity, and cardiomyopathy were anthracyclines' top 3 frequent AEs.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10757145/

AVA6000 could transform those statistics over the next decade.

In my view, if Avacta make the right choices, I think there’s at least a chance Avacta could get Fast Track Designation mid/end P1b based on its potential to address an unmet medical need for a serious condition. The unmet need being the fact that AVA6000 provides at least comparable efficacy (improved more likely) to the available therapy ie DOX while avoiding the serious side effects.

Drugs that receive Fast Track Designation from the FDA are eligible for

More frequent meetings with the FDA

More frequent written communication with the FDA

Eligibility for Accelerated Approval and Priority Review if criteria are met

Rolling review

In other words formalising the Avacta/FDA relationship with a view to accessing the Accelerated Approval pathway mid P2 perhaps!

FDA discussions about the evaluation of AVA6000 will not just revolve round efficacy data. The remarkable safety profile of AVA6000, is going to transform patient safety and, in particular, lessen or even overcome DOX-induced cardiotoxicity.

Despite how brilliant the trial data is I can’t see PFS being seen as a surrogate for OS at this point in time. Far too much heterogeneity in our small patient population. Of course the FDA might disagree!

Clearly the FDA accepts that PFS can be used as a primary endpoint instead of OS but as I understand it; very much depends on the cancer type/stage and any previous treatment(s). Yes, this endpoint is often used for studies of advanced-stage or metastatic cancer. In early breast cancer PFS is chosen but it’s not always used for advanced breast cancer. Advanced colorectal and ovarian cancer use PFS. However for ovarian cancer this is now being questioned and so it goes on! Different approaches for different cancer scenarios. A minefield basically! The research literature shows clear disagreements amongst oncologists especially over whether PFS should be used as a primary end point and furthermore, for a given cancer, views can and do change over time with the arrival of new data, improving treatments/ changing treatment types.

Pointless exercise trying to second guess how the FDA might be viewing our data with respect to Fast Track, Breakthrough Therapy or Accelerated Approval.

My take on this is very simple, listen to CC as was pointed out by SandyR.

CC made it crystal clear that more data is needed to de-risk the next step (P2).

“We don't know what the optimal indication is. We don't know what the optimal end point is, and we don't have the data to de-risk essentially moving there”

With regard using surrogate or intermediate clinical endpoints for AA. The example from the FDA below

“FDA may approve a drug based on evidence that the drug shrinks tumors, because tumor shrinkage is considered reasonably likely to predict a real clinical benefit. In this example, an approval based upon tumor shrinkage can occur far sooner than waiting to learn whether patients actually lived longer. The drug company will still need to conduct studies to confirm that tumor shrinkage actually predicts that patients will live longer.”

In this case you would need complete certainty that tumor shrinkage was the optimal endpoint BEFORE you start. Presumably this is the type of de-risking CC refers to so need p1b.

When you look at what’s at stake for Avacta ie the risk of utterly destroying the credibility of the pre|CISION platform and everything that follows from that, then Avacta have no choice but to push on relying on the guidance coming from Udai Banerji and the SAB. There are no shortcuts! Of course PFS could turn out to be the chosen endpoint come the end of p1b.

Avacta talking about a subset of STS so here’s an example of what a group of oncologists think about PFS as a clinical endpoint for DDLPS

https://www.esmoopen.com/article/S2059-7029(24)01256-0/pdf

Try reading it! Choosing an optimal endpoint is not simple!

Ice, however much you wish it true, this is not just a tick the box exercise for AVA6000. Sorr

Reckon there is plenty of robust discussion going on between Avacta and FDA

As I’ve said before Avacta are continually feeding new trial data into their exposure-response modelling and we know they’re using clinical utility index (CUI) calculations which is a valuable tool for evaluating the benefit-risk balance of a drug over a range of doses or concentrations. I’m sure there pushing this at the FDA but they may be facing a lot of resistance as this work tries to explain:

https://ascopubs.org/doi/full/10.1200/JCO-24-01372?af=R

https://ascopubs.org/doi/10.1200/JCO.24.00349

Meanwhile though, with Avacta having Udai Banerji on board at least we’re in safe hands in terms of navigating the best route to approval for AVA6000 when dealing with the FDA and project Optimus. At least UB has a track record since 2016 with regards to understanding the approaches that will enable Optimus implementation when designing early phase trials.

https://www.nature.com/articles/s41571-023-00853-z

https://aacrjournals.org/clincancerres/article/22/9/2127/79865/Are-Doses-and-Schedules-of-Small-Molecule-Targeted

Here’s the thing, we are over TWENTY YEARS on from the first ADC’s but only in the last few years have BP really started getting to grips with the challenges around “tuning” ADC performance by playing with its various components ie mAb, linker, payload etc and understanding how to, for example, exploit half-life extensions etc. Furthermore, ONLY in the last couple of years have we started to see the emergence of PDCs. The therapeutic benefits of PDCs are significant, but they have deficiencies too with poor stability, low bioactivity, leading to long R&D times and a slow clinical development process for this class of therapeutics.

All the more remarkable then that, seemingly overnight, Avacta have managed to develop a new pipeline of 10 additional assets using 2nd and 3rd generation preCISION chemistry that could potentially offer better outcomes than many of the developments achieved within the ADC/PDC arena that have taken big pharma nearly TWO DECADES to progress.

Quite incredible really!

The possibilities offered by modifying the chemistry built around the FAP cleavable peptide look to be game changing. CC had already explained to us how they can modulate the efficiency of the enzyme, and how it may be important to get different release kinetics and different PK depending on the class of warhead and the biology of how that warhead targets the tumor. The beauty of preCISION is it “designs” both the efficiency and rate of warhead release. Cytotoxic warheads ie DOX require higher efficiency/clearance to deliver intermittent high level in the TME whereas immunotherapy warheads are optimal with lower efficiency and slow clearance for sustained TME exposure.

The preCISION platform will prove itself to be priceless simply because it is so “highly tuneable”. As Curtis said “Using this approach the possibilities really are endless”. CC excited about “just the sheer number of ways we can use the preCISION platform”. Personally believe AS sat on the treasure chest that is the preCISION pipeline determined to keep hold of the key being unwilling to divert resources towards the new pipeline until he was ready! Ultimately the battle was won by CC and not surprisingly NB/FM keepers of the “old pipeline” have now been replaced.

Some clearly don’t get the “pathfinder” concept and the difference between clinical strategy for AVA6000 using DOX (dictated/driven by FDA Project Optimus) versus development strategy for the preCISION platform and its pipeline underpinned by the AVA6000 clinical data. We needed the data. We have three years of data and thanks to the highly talented team of scientists, oncologists and various consultants involved Avacta are using that data to build a revolutionary new platform to overcome many of the limitations of current ADCs, enhancing the precision and efficiency of drug delivery to the TME and cancer cells within.

As I’ve already said it’s bloody complicated! Avacta working

Avacta doing a good job in providing simple explanations to help investors understand AVA6000 and the preCISION platform science. Too simple?

Many complicating factors surround preCISION, AVA6000, DOX and its delivery into the TME but there is one that stands out and directly influences Avacta’s clinical strategy.

HETEROGENEITY! Particularly tumour heterogeneity ie chemo resistance. This is one factor that haunts all oncology trials and is often a major barrier to success. We know chemo resistance is a particular problem with DOX. In fact, it is estimated that up to 50% of patients eventually become resistant to anthracyclines.

So simple and yet so very complicated!

Reversing chemotherapy resistance in pancreatic cancer | Stanford Report

The extracellular matrix alteration, implication in modulation of drug resistance mechanism: friends or foes? - PMC

Doxorubicin and other anthracyclines in cancers: Activity, chemoresistance and its overcoming - ScienceDirect

The thing is the scientists’ understanding of the TME, stroma, extra cellular matrix, is constantly evolving wrt physical and chemical/ biological processes in a way that continually highlights the basic need for a TME targeting platform which can exploit this knowledge thus leading to more therapeutic options for various cancers.

Personally believe this new knowledge will help ensure the potential of preCISION will be exploited, especially combo treatments, dual action, multiple targeting! BP scientists will still be mulling over all the various possibilities.

Stealing the conclusion from above source

“Ultimately, a new frontier will be possible with the discovery of cancer-selective molecules, and in particular with tumor-selective delivery of drugs. We think that tumor vs. normal cells selectivity will be the next important barrier that needs to be overcome…”

I think we can legitimately claim that preCISION has already overcome this barrier.

Meanwhile, AVA6000 is still very much a “Pathfinder” drug. Avacta using the chemo warhead doxorubicin to consolidate the validation of Avacta’s platform technology and open up a new pipeline of pre|CISION drugs applicable across, chemo, immuno and radio therapy. Oh! We also get a "Brucie Bonus" with AVA6000 becoming a SOC replacement for dox.

we’re all waiting for the next bit of advice from our resident scarecrow!

“do you actually research the other promising cancer treatments?”

“it isn’t research unless it considers the wider picture.”

“customised anti cancer vaccines will blow chemotherapy out the water in a few years time.”

seriously! these novel immunological approaches to treatment and prevention are often unique to the individual patient. there are so many variables from patient to patient that it is almost certain that this approach to treatment will join, not replace, the current therapeutic ****nal.

in fact if you do the basic research required to understand cancer vaccines you would soon discover that almost every review offers a similar viewpoint going forward; much of the focus in the development of cancer vaccines will shift towards the use of vaccines as combinatorial treatments with eg immune checkpoint inhibitors and/or other approaches such as chemo- and radiotherapy.

“it is becoming increasingly more apparent that, as part of the design of vaccine regimens, combination therapy might be a better treatment option compared to monotherapy for durable clinical responses. combination regimens currently being explored include differing immunotherapeutic approaches including vaccines combined with conventional chemotherapy and radiation therapy.”

“clinical responses generated by cancer vaccines are heavily governed by indication, antigen selection, patient‐specific factors, vaccine type, and combination therapies. our evaluation (2023) of ongoing clinical trials indicates that adept attention to all these factors will be a major determinant of the future success of cancer vaccines. because many cancer vaccine trials often take years to proceed from each clinical phase to the next, the current analysis does not yet reflect many promising preclinical interventions, including novel adjuvants and drug delivery carriers. although clinical results have been disappointing to date, the latest data indicate that there may be a more permanent niche for vaccines in the expanding repertoire of therapeutic interventions against cancer.”

cancer vaccines will simply be another tool in the box alongside chemotherapy, radiotherapy and other immunotherapy approaches at least for the next decade or so.

https://www.mdpi.com/2076-393x/11/12/1783

https://www.mdpi.com/2076-393x/6/3/52

https://www.ncbi.nlm.nih.gov/pmc/articles/pmc10771564/

if you are going to take your lead from sunday press articles the least you can do is check out the relevance and filter out the hype!

One thrust of CC’s excellent presentation was to open the shop window for the preCISION platform as a whole. Highlighting the fact that Avacta can “implement the precision technology essentially in three different platforms” using the small molecule PDC approach ie preCISION alone, then preCISION+ (extended half-life) through to a biologic targeted approach with affimer drug conjugates and preCISION ADC’s (dual delivery).

Continued accumulation of clinical data for AVA6000 will serve to emphasise the fact that the preCISION chemistry works ie it’s safe and highly tumor specific but added to that is the wealth of possibilities that potentially exist for application of the pre|CISION technology . This needs to be recognised. A powerful delivery platform because it can be leveraged in different formats, designed/ tailored to meet specific needs and provide optimised/precise delivery of a payload (anticancer drug or warhead) to the tumour.

Here’s the really important thing; pre|CISION might just happen to be the enabling tool that unlocks new therapies over the next decade, particularly with regard combination therapies. Below is an example where a highly innovative therapy is being compromised by an inability to deliver it safely, directly to the tumour.

What if the future is all about in-situ therapeutic cancer vaccines as a mode of treatment. In-situ vaccination (ISV) involves delivering a combination of drugs to stimulate immune cells along with an intervention that kills cancer cells, such as radiotherapy, directly to an individual’s primary tumour.

“Although the developers of the personalized mRNA cancer vaccines that currently hold centre stage see their bespoke approach as viable, creating bespoke therapies for every patient is expensive. The beauty of ISV is that the treatment is identical for everyone, but the result is still immunization against each person’s unique cancer.”

Apparently ISV needs to show its readiness for commercial development by overcoming the major problem of needing delivery via intratumoural injections.

“The solution, they say, is to chemically link dendritic-cell-targeting drugs to antibodies or other molecular partners that accumulate inside tumours after being given systemically.” In this case a TLR9-activating drug coupled to a peptide travelled to tumours in mice and shrank these cancers without systemic side effects.

That all sounds familiar because they’re talking about using drug conjugates for safe targeting of the tumour.

https://www.nature.com/articles/d41586-024-01429-2

In other words there’s plenty of exciting drug development work going on out there and who’s to say that some of what emerges over the next few years won’t incorporate use of preCISION for safe precise targeting. PreCision can remove obstacles!

Really looking forward to the release of the updated pipeline. Be interesting to see what Avacta themselves have come up with regardi

April 24 CC presentation of AVA6000 poster AACR2024 see Figure 7

Also reproduced in the latest TP research note see bottom page 8

This is what CC had to say:

“So taken together all of these, observations in this figure, we see responses with AVA6000 at doses with doxorubicin exposures here that are much lower than that which is reported with standard dose doxorubicin……

This suggests that perhaps more frequent administration of those lower doses where we observe the responses could increase the efficacy and may still, limit the toxicity, that we observe. And so this figure, and the observations that we've made in the every three weekly regimen really underscore and highlight the possibility of the every two weekly regimen being, more favourable in terms of efficacy and safety.”

Referring to exactly the same figure in the 28th May TP research note we now have:

“The unequivocal conclusion is that a more frequent schedule of AVA6000 doses may enhance efficacy without a coincident increase in toxicity. A significant improvement in DOX’s therapeutic window (or ‘index’) has therefore been achieved.”

Hmmm! Showing a lot more confidence wouldn’t you say!

“In expressing a high level of confidence that results from the ongoing two-weekly dosing schedule plus follow-on expansion study will build conviction in pre|CISION™’s unique ability to concentrate a Doxorubicin (‘DOX’) warhead in the tumour microenvironment (‘TME’) while sparing healthy tissue and dramatically reducing toxicities, the Board recognises its highly protected technology has potential to become a ‘holy grail’ of next generation cancer medication.”

Definitely! A lot more confidence!

Avacta are continually feeding new trial data into their exposure-response modelling. Now they’re using clinical utility index (CUI) calculations which is a valuable tool for evaluating the benefit-risk balance of a drug over a range of doses or concentrations.

https://ascopubs.org/doi/10.1200/JCO.22.00371

The statements from our resident Windbag and eggy are so so wrong and such an insult to all those involved with AVA6000; especially the patients.

Justification for the 2W study has nothing to do with a sudden need to alter dosing regimes due to a lack of effectiveness. We have a clear scientific rationale.

You simply don’t “bugger about with dosing regimes” for God’s sake. Finding the optimum dose is not a trivial ticking boxes exercise as some would have you believe! Lots of complexity to be dealt with often using sophisticated models that few here would fully understand, including me!

Having a rigorous dose optimisation phase is absolutely critical for the success of both AVA6000 and the PreCISION platform. Avacta have to get this right and the implementation of the 2W study and a subsequent dose expansion is all part of the process.

It takes as long as it takes!

Taken this from the link BV kindly provided on ADC toxicity.

Unwanted toxicity restricts the clinical benefit of ADCs by limiting the tolerable doses to amounts below the levels required to provide meaningful or optimal anti-cancer efficacy. In a formal comparison of effective exposure levels identified in preclinical studies with exposure profiles at the maximum tolerated ADC doses in the clinic, de Goeij and Lambert concluded that, for many ADCs, the exposures at the clinical MTDs were significantly lower than the exposures required for efficacy in preclinical models. Much focus in the ADC field is shifting to strategies to widen the therapeutic window through the mitigation of ADC toxicity, as this approach, if successful, might enable increased MTDs and subsequently improved clinical outcomes.

The way I see it, despite all the efforts being put into improving the ADC toxicity/efficacy profile there always seems to be a real need for better pre-clinical to clinical translation.

If Avacta can nail down their understanding of FAP and show consistency and predictability in their modelling when moving from lab to clinic then the advantages of the pre|CISION platform on offer to BP become even more compelling. That’s one reason why I think the value of the platform will rocket when 3996 goes into the clinic; proof of predictability!

Avacta is building a platform based pipeline of novel cancer therapies - pre|CISION drug conjugates - with the potential to revolutionise the treatability of solid tumours. Where to position the products? And how best to develop them?

I found this an interesting read adding to the background picture.

https://www.zs.com/insights/oncology-antibody-drug-conjugates-revolution

Avacta stepping up to the plate giving the shop window a makeover wanting to show that the pre|CISION platform has the potential to be right up there at the front of oncology’s next revolution.

It’s all about ****Platform potential****.

“A platform approach to drug discovery and development, whereby drug manufacturers leverage a common platform to produce multiple new therapeutics with reduced need for asset-specific add-ons, has been shown to speed time to market and deliver substantial cost efficiencies. In fact, ZS analysis has found that platform companies, on average, add subsequent pipeline assets between three and eight months faster than non-platform companies—and at 40% lower R&D cost.
 

The modularity of ADCs makes for an ideal platform. Take, for example, Daiichi Sankyo’s DXd ADC platform, headlined by ENHERTU. It took the company just over five years to go from first-in-human trials for ENHERTU to first-in-human trials for its fifth ADC. For non-platform companies, the average apples-to-apples time is more than seven years”.

I want to see Avacta go as far as they can with their platform technology.

Looking at first in class oncology drug innovations from small biotechs (FDA approved 2010 to 2022) the journeys taken between discovery and launch vary widely.

What happened to the small biopharma companies?

35%, eventually fully acquired by a large pharma.

13%, licensed worldwide rights to the development and commercialization of the asset to a large pharma company.

4%, retained the US rights but licensed ex-US rights to large pharma.

9%, co-commercialized the drug in the US with a large pharma partner.

22%, licensed the asset to a different small pharma entity, but in most of those cases, the new small pharma owner then partnered with medium or large pharma companies for commercialization.

Only 17% completed the development and launch of the drug they discovered.

After many years trudging through the foothills Avacta finally starting its journey to the summit. Going to be hard slog until BP turns up, which they will eventually!

GLA

Well, there we have it, the point I was trying to make earlier today, pre|CISION can be utilised in multiple drug formats:

pre|CISION, pre|CISION PDC, pre|CISION+, pre|CISION ADC…..

Wow! Wow! Wow!

The only problem now is my ageing brain is rapidly reaching its limit in terms of ability to digest and take on board the rapidly expanding detail of what pre|CISION potentially offers, and what it will compete with in the targeted drug conjugate arena.

Here’s a sample tutorial, good luck!

https://www.researchgate.net/publication/365050206_Non-internalising_antibody-drug_conjugates/fulltext/63672bc154eb5f547ca916c1/Non-internalising-antibody-drug-conjugates.pdf?origin=publication_detail&_tp=eyJjb250ZXh0Ijp7ImZpcnN0UGFnZSI6Il9kaXJlY3QiLCJwYWdlIjoicHVibGljYXRpb25Eb3dubG9hZCIsInByZXZpb3VzUGFnZSI6Il9kaXJlY3QifX0

One thing really caught my attention though, see page 10!

Having previously dismissed Dr Paul Loadman’s interest in Matrix metalloproteinases (MMPs), a family of endoproteases that are overexpressed in tumours, I can see possibilities for a pre|CISION-ADC built around MMP’s.

The dual-delivery by a pre|CISION-ADC drug leveraging both MMP9 to target via antibody (maybe even an Affimer) and FAP to release the cytotoxic drug payload. Yes I know traditionally ADC’s target antigens but

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6582441/#cbic201800623-bib-0021

Monoclonal antibodies selective for specific MMPs have been successfully generated.

https://www.sciencedirect.com/science/article/pii/S0945053X15000037

The Avacta pre|CISION-ADC platform leverages the FAP-activated tumour-specific release mechanism of the pre|CISION technology (to release a suitable cytotoxic payload) with the tumour-targeting capability of an antibody (or Affimer) for MMP’s.

Could it be? Exciting times ahead!

“The overarching message that data from AVA6000’s Phase 1a trial delivered on 13 Dec 2023, was that the pre|CISION™ platform works exactly as it was designed to. In this respect, its potential to change the way in which potent cytotoxic drugs are delivered, therein improving cancer patients' quality of life and treatment outcomes appears quite remarkable.”

AVA6000 pathfinder and 3996 follow up unlocking the pre|CISION platform.

pre|CISION unlocks delivery of more potent warheads/payloads.

pre|CISION medicines will open up future opportunities for combination therapies.

pre|CISION promoted as a major breakthrough spearheading growth of FAP based therapies for FAP expressing cancers.

pre|CISION + FAP will unlock future possibilities for targeted therapy.

pre|CISION + FAP will open up TME activated conjugates (TMAC).

TMAC opens up new immunotherapy possibilities.

Avacta are no longer walking a path of uncertainty. Deliberately shifting AVA6000 from a chemo prodrug to a peptide drug conjugate ensures that the spotlight is well and truly focused on the pre|CISION platform and the multiple possibilities for exploitation. Avacta are deliberately aligning the potential of pre|CISION with that of the much sought after ADC’s (PDC’s) whose market analysis, global forecasts, and acquisitions clearly demonstrate significant (frenzied !) demand by BP to fulfil a vast potential market.

The accumulating clinical data will continue strengthening models of behavior and is likely showing enough predictability to warrant this pivot in strategy and change in messaging. Has a robust clinical model to predict patients’ response to a pre|CISION treatment been realised? Green light for building out the pipeline.

AVA3996 into clinic 1H25

Further expand pre|CISION pre-clinical pipeline

Next clinic candidate selected 1Q25

TME activated conjugate. Clinical candidate selected 2H25

You don’t claim “it works” and expand pipeline without having the necessary pillars of supporting evidence firmly in place. First and foremost, maximum confidence that more than adequate levels of any payload will be released in the tumour micro environment ie the amount of payload available to the tumour cells will be sufficient to cause significant cytotoxicity. Secondly, a high level of confidence in future ability to measure levels of FAP plus understand impact of FAP distribution and heterogeneity on pre|CISION performance.

Bold statements being made by Avacta suggests really positive data and a firm grasp on these two factors which collectively determine the likelihood of success for a pre|CISION conjugate.

Roll on April 10th!

Purely coincidental !

It looks like back in 2015/16 Avacta had a science writer plus Paul Ko Ferrigno, the chief scientific officer, regularly churning out stuff in the news slot to promote affimer technology and antibody alternatives and so just happened to write this piece on the ECM. With MMPs largely responsible for driving cancer progression and playing a key role in remodelling the TME it was obviously relevant to the messaging “strategies for developing therapeutic antibodies to targets within the ECM have not gained much favour”.

Yes incredibly familiar isn't it!

https://eprints.ncl.ac.uk/file_store/production/240398/B5831AD6-D635-4A2A-A0C6-888401A9C506.pdf

Clearly this guy has the potential to put serious input into Avacta’s knowledge base. He obviously has a deep understanding of protease activated prodrugs and the complexities of the TME besides having an interest in being able to unravel targeting drug distributions and penetration through tumours and normal tissues. Then there’s his specialist knowledge of pharmacokinetics and drug metabolism.

I don’t think Avacta knocked on his door just to ask him to look over some biopsy data; there will be a lot more to it. Helping Avacta with the underlying story around the pre|CISION MOA, FAP expression and drug distribution in the tumour all aimed at building up the pre|CISION platform IP.

In a previous post I highlighted a recent study showing FAP activity can be quantified non-invasively (in serum) by the novel biomarker C3F using C3F ELISA assay study.

https://www.mdpi.com/2227-9059/12/3/545#:~:text=In%20this%20study%2C%20the%20C3F,for%20C3F%20as%20a%20biomarker.

Avacta have mentioned looking at biomarkers and are stating “Correlative studies demonstrate high FAP expression in the tumour tissue” suggesting they are finding ways to determine the levels of FAP in the tumour tissue. Could Avacta combine bio marker studies with data from the analysis of biopsy tissue samples to really nail down the FAP levels for pre|CISION function which would massively increase the value of its IP?

Regardless of the above with both PL and a specialist pk/pd modelling team (thinkQ2) on board it must open up a few possibilities.

Some biomarkers just attempt to predict from the properties of the tumour whether it is likely to respond to a particular treatment (such as C3F marking FAP levels) but other so called pharmacodynamic (PD) biomarkers provide a measure, posttreatment, of whether the drug has reached its target and exerted a pharmacological response, and if so, what was the degree of response.

PD biomarkers can be used to make quantitative decisions, for example, to adjust the dose, or change the schedule of administration, via an appropriate PK/PD model.Apparently biomarker measurements are becoming standard in phase I clinical studies, and investigators are increasingly starting to fit their biomarker data to PD models.

All just food for thought!

Well I finally got round to looking up Dr Paul Loadman to try and work out where Avacta might be directing his consultancy expertise.

Firstly PL is part of the University of Bradford Institute of Cancer Therapeutics where Prof Twelves is an honorary professor. They’ve worked together on Mass spectrometry imaging (MSI) a relatively new and complex technique that allows imaging of drug distribution within tissues to understand whether a drug is being adequately delivered to the tumour.

https://www.sciencedirect.com/science/article/abs/pii/S104084281930126X

Secondly PL has first-hand experience of developing protease activated prodrugs.

Whilst pre|CISION is cleaved by FAP, which is a serine protease, it seems PL is also pursuing the science behind proteases in cancer drug delivery. His specific interest is in developing matrix metalloproteinase (MMP) activated therapeutics. He has various patents dating from 2008 on prodrugs of vascular disrupting agents activated by MMP cleavage.

“Matrix metalloproteinases (MMPs) are a family of endoproteases that are overexpressed in tumours and play crucial roles in many tumourigenic processes, not least tumour invasion and angiogenesis. The concept behind our technology is that the increased expression and activity of MMPs within the tumour microenvironment, relative to normal tissues, can be exploited to selectively release potent chemotherapeutics from non-toxic peptide conjugates. The result is high levels of the active agent in the tumour and negligible drug levels in ’normal’ tissues”.

“Conjugation of a peptide to the active drug molecule renders it inactive until such time that it is activated by MMPs in the tumour. The MMP then cleaves the peptide, resulting in release of the active drug selectively in the tumour microenvironment”.

That all sounds incredibly familiar doesn’t it!

If you’ve got the time it’s worth a watch. Good bit on MIDD the behind the scenes stuff we don’t get to hear about but it’s the pre|CISION™ platform engine room!

Start at 5.00 min

https://youtu.be/8o7lQCrS4pc?si=0Zjm6PDwrbSTFwID

The thing is we just don’t know and Avacta won’t tells us!

It’s the same with regards all this crap around; it’s a safety trial! It’s about safety and efficacy! It’s not an efficacy trial! It’s a safety and tolerability trial! It’s………and so on!

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868302/

There are plenty of traditionalists who continue to believe that a P1 trial is purely about safety/ tolerability and won’t be persuaded otherwise. However this view is being challenged by many others who believe P1 trials can provide “a preliminary indication of the therapeutic value” (note the very careful language used).

Avacta find themselves caught up in a moment in time where there is a definite move to strike a better balance between drug safety and efficacy in the design of P1/P2 trials. In particular collecting data for patients with the disease intended to be treated by the intervention so can also provide valuable initial indications of therapeutic activity.

Yes P1 is primarily about safety and finding the highest dose of drug that can be given safely without causing severe side effects but increasingly P1 includes therapeutic activity. Avacta’s phase 1 trial was also intended to evaluate early efficacy of AVA6000 ie whether the treatment in question is effective.

“A Study Evaluating the Safety, Pharmacokinetics and Early Efficacy of AVA6000 in Solid Tumours with ORR, DOR, PFS and OS being efficacy measures.”

Avacta are currently treading very carefully and any efficacy signals are communicated very cautiously ie “AVA6000 is already showing encouraging preliminary clinical signs of anti-tumor activity”. So promising early signs of efficacy are being observed.

The simple fact is ALL data gathered will be evaluated by the FDA who have been known to grant approvals on the basis of results from P1 studies.

That’s the problem 2016; things have moved on!

You could try spending some time reading the research that’s already been posted by many others on here!

Trial is going to plan but the plan is controlled by the FDA.

Try having a read of this lot to set the scene!

https://www.hallorancg.com/2024/02/22/fda-project-optimus/

https://friendsofcancerresearch.org/wp-content/uploads/Optimizing_Dosing_in_Oncology_Drug_Development.pdf

https://friendsofcancerresearch.org/wp-content/uploads/Early_Phase_Oncology_Trials_Optimal_Dose.pdf