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Focus has always been the pipeline in the eyes of LTH’s



Licence AVA6000 to fund it has always been obvious to all LTH’s



Most likely partner Novartis. Proves you can read what others were saying!


“I wish I’d thought of that. Oh hold on. I did, a year ago”

Yeah, what took you so long?

You’ve only ever wanted to push a Novartis buyout at £1 or whatever. 🤡

One of many on X going into overdrive speculating on Avacta’s potential strategies for partnering and licensing deals etc

Can’t deny it certainly seems odd that Avacta have dropped all things STS recently.

I’m not a betting man, but if I had to back a potential candidate for a STS deal, who would it be?

Obvious suggestion has been Eli Lilly and the possibility they may want to look for a replacement for Lartruvo (olaratumab) which was withdrawn for the STS indication in 2019.

However, I’m going for a deal with Novartis,

Pazopanib (tyrosine kinase inhibitor) is their approved drug for use as a monotherapy for adult patients with STS who have previously received chemotherapy doxorubicin so it’s a second line treatment.

One study in elderly patients (over 60) found that pazopanib had a better safety profile in terms of neutropenia and febrile neutropenia compared to doxorubicin suggesting that pazopanib could be a suitable first-line option for elderly patients with STS.

Also, a couple of studies have shown that pazopanib when used in combination with doxorubicin, may potentially improve patient outcomes.

Novartis's pazopanib, marketed as VOTRIENT, saw global sales of $635 million in 2020, a 16% decrease from 2019. Estimated annual sales of $188 million in the US in 2023. That’s the only data I could find!

Declining sales which would certainly be eaten into by AVA6000 and a possible combination therapy which could be further explored. Reason enough?

Yeah, it’s Novartis for me!

I wish!

Ben, they’re chasing ghosts! Desperately wanting to push the assumption that short half-life must be detrimental to the performance of AVA6000.

The half-life of drug conjugates is just one of the many factors that influence efficacy. The ideal half-life depends on the specific conjugate construct, its payload, and the characteristics of the target tumor. The goal is to find an optimal balance between efficacy and toxicity, which is known as the therapeutic window.

For AVA6000 DOX this goal has been achieved which allows Avacta to turn something that could have been seen as sub optimal into a real positive. In their slide deck they even describe it as

Advantages. • Short plasma PK of the PDC (t1/2 minutes to hours).

Basically the pre|CISION® platform allows for the design of both the efficiency and rate of warhead release. Tuneable half-life when it’s needed no less! Win! Win!

Genuine SH’s will want to focus on any positive aspects.

Others! They will want to dwell on any perceived disappointment.

Same old merry go round!

Bright side, a new ISA contribution is inching ever closer! How many more Golden Tickets I ask myself?

I’m sure he would battling against this trio of Russian assets!

Agent Orange plus Son Of Orange and The Ketamine Kid.

We’re all battling against the falsehoods!

Cindercone you’re absolutely correct. Guilty as charged!

But despite reporting/ ignoring them they’re still here.

Never mind I’ve given your post a rec just like I have for all the other posts on ignoring this trio which have appeared so regularly over the past few years.

Let’s face it there’s only one simple solution. Avacta taking away their ammunition.

The sooner the better!

The Big Boys like to go for their fireside chats. Didn’t you know!

https://investor.lilly.com/news-releases/news-release-details/lilly-participate-leerink-partners-global-healthcare-0

Eggy boy, if it’s ok for all of big pharma to use these “slippery words” then so can Avacta.

Fortunately us genuine shareholders fully understand all this slippery talk.

I’ll help you out here just this once.

The term "multiple patients" is a standard and commonly used term within the vocabulary of clinical trials and clinical research, referring to a group of participants in a study. 

The term "significant" is a standard vocabulary term used in clinical trials, often referring to statistically significant findings or results that are meaningful and unlikely to be due to chance.

In cancer treatment, a "significant" level of drug in tumor refers to a medication that has demonstrated considerable effectiveness in shrinking or controlling tumors, often through targeted therapies or chemotherapy.

Really Eggy, you should give up and put your DK book away. The “Help Your Kids with Science Guide” is not going to help you with this slippery science stuff no matter how many times TW reads it to you.

Avacta have to navigate the TNBC patient terrain shown on what CC called her “ugly” slide.

R and D Spotlight Live Science Day Event – October 2024 – slide 46 in slide deck

Need to listen from 32:22 to 36:05 in the video.

The slide shows the patient populations where systemic chemo is used for TNBC and CC explains why “TNBC is important part of the AVA6000 development scheme going forward”.

She also highlighted the treatments particularly in 3L where she expects ADC’s will continue to evolve.

In the TNBC disease setting using chemo a major hurdle has always been the need to overcome doxorubicin resistance and side effects (cardiotoxicity). This led to the use of Merck’s Keytruda plus chemo mentioned in the slide (eg Keynote 522 regimen).

More recently some studies suggest the use of dose-dense (14 day) doxorubicin within modified Keynote 522 protocols may be superior leading to better patient outcomes. This likely prompted the need for our q2week dosing study and suggestions about the use of AVA6000 in such combo treatments.

It’s not unreasonable to think Avacta could have two bites of the TNBC cherry!

It’s also hard to imagine Merck wouldn’t be interested in AVA6000 in a combo treatment.

Given the potential here I would still expect some expert TNBC input beyond that from Chris Twelves and the current SAB.

Looking at Avacta’s Scientific Advisory Board (SAB)

SGC

Dr. Ho @Memorial Sloan Kettering

Dr Metcalf @The Christie Hospital

STS

Dr William D. Tap, MD @Memorial Sloan Kettering

Dr. Lee Cranmer @Fred Hutchinson Cancer Center

Dr. Andrea Napolitano @The Royal Marsden

Professor Robin Jones @The Royal Marsden

TNBC

? Not needed?

I keep wondering why there’s still a glaring hole in Avacta’s line up of oncology advisors; a situation which is not in keeping with their usually rigorous scientific approach. The SAB is one positive they have for inspiring investor confidence.

I know it was a late pivot to include a TNBC expansion cohort in P1b and we still speculate on why that sudden move but I would have expected Avacta to appoint someone to the SAB to take the lead on TNBC.

Since TNBC patients in P1b are now being dosed I wonder who exactly is providing overall guidance for AVA6000 in TNBC during this critical phase 1 expansion study?

Surely expert input from TNBC oncologist(s) is needed to help guide Avacta’s clinical development decisions for this disease setting just as it is for SGC and STS.

Someone must be casting an expert eye over the incoming TNBC data to go alongside CC’s views on what is emerging and its implications for partnering etc.

Have Avacta set off down the road still needing to attract a partner for TNBC or is there a prospective partner already being given access to the data lessening the need for any SAB specialist input.

Alternatively maybe Avacta pulling in an external consultant for TNBC guidance in keeping with the idea it’s being neatly packaged up separately from SGC/STS with the expectation it will be partnered post P1b data release.

You have to wonder what’s going on here. First read out of P1b data for the TNBC arm and then the story should start to unfold.

Not so quite perhaps!!

https://twitter.com/Littleboyblue75/status/1894457927676625252?ref_src=twsrc%5Etfw

TwiX folks believe Exatecan will be the chosen topoisomerase 1 warhead and seem convinced Daiichi Sankyo’s relationship with Avacta will develop into some kind of partnership. Don’t disagree it’s a possibility. However if you follow DS they already have their next generation ADC in the clinic and furthermore are executing on their future plans for drug conjugates since preparations are already in progress for FIH with their yet to be disclosed “New-Concept ADC”. Is it us? Very much doubt it!

I’m hoping Avacta have gone for broke with the new pipeline and pulled in what might be the mother of all warheads; a pyrrolobenzodiazepine (PBD) based payload.

PBD is a highly potent DNA damaging agent (IC50 ~ ‭ ‬pM) ‭compared ‬to the lower potency ‭of the ‬topoisomerase I inhibitors (IC50 ~ nM) ie 1000x more potent. FDA found that nearly 50% of IND applications for PBD-conjugated ADCs between 2013 and 2017 were discontinued, mainly due to safety concerns.

By the way Daiichi Sankyo’s “next generation ADC” is DS-9606, a modified pyrrolobenzodiazepine (PBD) ADC, targeted to CLDN6 and is now in P1 trials.

Back in 2021 Avacta told us that multiple additional programmes being explored as part of TMAC. Talking about Affimer-drug conjugates that combine a PD-L1 inhibitory Affimer linked to a variety of other anti-tumour groups, such as STING agonists, TLR 7/8 agonists, and PBD and Auristatin toxins. With prior experience of linking to these drug moieties in the bag I’m anticipating these warheads might appear in the new pipeline.

Many second-generation ADCs used the more potent tubulin inhibitors as payloads auristatins (MMAE) being one of the the many examples. Unfortunately, while tubulin inhibitors are very effective against actively dividing tumor cells, they are much less effective against static cancer cells. To potentially overcome this limitation, DNA damaging agents (eg PBD), which can target the whole cell cycle, were selected as the cytotoxic payloads for many of the third-generation ADCs.

The thing is; more diverse payloads such as immune modulators ie STING agonists, TRL7/8 agonists along with PBD and Auristatin toxins etc are very much the basis for the ADC’s currently being developed by BP. What better way to go head to head with ADC’s and scare the pants off BP than to present in vivo data for next generation PDC/AffDC platform products that BP can better compare with data from their own ADC’s. I’m really hoping a few comparable ADC’s were included in some of the in vivo studies that have been carried out with the new preCISION warheads.

B2HS2L I very much doubt; far too busy with the new pipeline!

I maybe completely wrong but really it’s a case of Avacta covering all bases to protect their IP. Companies wanting access to the technology may try to get around the patent for example by claiming use of a novel delivery method. Hence Avacta need to include all known possibilities.

Really just trying to make the point that Avacta have a technology stable offering real depth and breadth far removed from being just a one trick chemo revival company as some would try to have you believe.

The envelope is already being pushed with Affimers via Prof Tomlinson’s group who have already started work with Affimer-MMAE conjugates and HER2-binding affimers.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11298639/

We all know about AffyXell work where stem cells are genetically modified to produce and secrete therapeutic Affimer® proteins with immuno-modulatory effects in situ in the patient.

Found this bit of the scaffold protein patent interesting

Encoded AFFIMER® s for In Vivo Delivery


An alternative approach to the delivery of therapeutic AFFIMER® polypeptides would be to leave the production of the therapeutic polypeptide to the body itself. A multitude of clinical studies have illustrated the utility of in vivo gene transfer into cells using a variety of different delivery systems. In vivo gene transfer seeks to administer to patients the “Encoded AFFIMER®” nucleotide sequence, rather than the AFFIMER® polypeptide. This allows the patient's body to produce the therapeutic AFFIMER® polypeptide of interest for a prolonged period of time, and secrete it either systemically or locally, depending on the production site. Gene-based Encoded AFFIMER® s can present a labor- and cost-effective alternative to the conventional production, purification and administration of the polypeptide version of the AFFIMER® polypeptide. A number of antibody expression platforms have been pursued in vivo to which delivery of Encoded AFFIMER® s can be adapted: these include viral vectors, naked DNA and RNA. Encoded AFFIMER® gene transfer can not only enable cost-savings by reducing the cost of goods and of production, but may also be able to reduce the frequency of drug administration.


The tumor presents another site for Encoded AFFIMER® transfer, targeted either via i.v. or direct injection/electroporation. Indeed, intratumoral Encoded AFFIMER® expression can allow for a local production of the therapeutic AFFIMER® polypeptides, waiving the need for high systemic AFFIMER® polypeptide levels that might otherwise be required to penetrate and impact solid tumors. A similar rationale applies for the brain, which is frequently targeted in the context of antibody gene transfer to avoid the difficulties with blood-brain barrier trafficking and would likewise be a target for delivery of Encoded AFFIMER® s.


The success of gene therapy has largely been driven by improvements in nonviral and viral gene transfer vectors. An array of physical and chemical nonviral methods have been used to transfer DNA and mRNA to mammalian cells and a substantial number of these have been developed as clinical stage technologies for gene therapy, both ex vivo and in vivo, and are readily adapted for delivery of the Encoded AFFIMER® s of the present invention.

Interesting stuff! The fudsters keep talking about the threat of competition from therapies of the future not realising Avacta itself has the opportunity to very much be part of that future via use of Affimers.

There are a number of different Avacta patents out there so difficult to follow what’s going on but interesting to flip through Avacta’s patent for Scaffold Proteins 26/09/24. A small section on AFFIMER®—Drug Conjugates


“Therapeutic agents that may be attached to AFFIMER®-containing polypeptides include, but are not limited to, cytotoxic agents, anti-metabolites, alkylating agents, antibiotics, growth factor, cytokines, anti-angiogenic agents, anti-mitotic agents, toxins, apoptotic agents or the like, such as DNA alkylating agents, topoisomerase inhibitors, endoplasmic reticulum stress inducing agents, platinum compounds, antimetabolites, vincalkaloids, taxanes, epothilones, enzyme inhibitors, receptor antagonists, therapeutic antibodies, tyrosine kinase inhibitors, radiosensitizers, and chemotherapeutic combination therapies……”

“Non-limiting examples of Topoisomerase I inhibitors include Campothecin derivatives including CPT-11 (irinotecan), SN-38, APC, NPC, campothecin, topotecan, exatecan mesylate, 9-nitrocamptothecin, 9-aminocamptothecin, lurtotecan, rubitecan, silatecan, gimatecan, diflomotecan, extatecan, BN-80927, DX-8951f, and MAG-CPT……. “

On and on it goes, listing many hundreds of examples of specific therapeutic agents that can be linked to the Affimer.

So many choices! Truly the case that “the possibilities are endless.”

Might be of interest to some here with Avacta seen as both product and platform company

http://leadershipandbiotechnology.blogspot.com/2018/08/early-stage-biotech-value-creation_15.html

“The appropriate financing strategy will be dictated by internal forces (the nature of your assets and vision) and externalities (the partnering and capital markets).

There is no single strategy appropriate to every company in every environment. At the same time, the fact of the matter is that, in the period before you have product revenues, you have only two things to sell.

The first is technology and information of current value to the customer (typically, a larger biopharmaceutical company).

The second can be called “futures,” and those futures come in one of two flavors: equity (and instruments that look, smell, and taste like equity) and rights (marketing/profit participation rights) in/to the products (and the revenues they will produce) you are seeking to develop.

As it were, you are selling participation in the future financial appreciation of the whole and/or of one or more of the parts. (Note: the sale of technology and information of current value to the customer can and most often involves a sale of rights.)

Value creation is not about the size of your market cap, or not directly about that. It’s all about share price appreciation.

You can create a large market cap without creating shareholder value by taking too much dilution early when your stock price is at its lowest. Therefore, be wary of early dilution.

Yet beware that corporate partnerships are not an end in and of themselves and are not a (purely) “non-dilutive” form of cash; they are an implement of strategic value creation.

Use them to contain early dilution but only if you can do so in a manner that does not give away the major sources of your future value creation.

Ours is a business in which you can spend yourself to death, but you can’t save your way to glory.

Therefore, under-spending/under-capitalizing and over-spending/over-capitalizing both represent sources of risk to exceptional value creation.

The art lies in balancing the two different sources of capital as they represent two different forms of dilution and in recognizing the relative risk of the two that applies to your specific situation.

Identify your specific situation at the given moment in your evolution and act accordingly.”

Precisely that:

As SC stated “Our longer-term financing strategy is being formulated”

Old news! Yeh right! You can’t see it and that speaks volumes.

For Avacta this was at the top of the rns

“Multiple ongoing and durable RECIST responses observed in patients with FAPhigh and doxorubicin sensitive diseases including in patients with stroma-only expression of FAP”

“in patients with stroma-only expression of FAP”

Well that’s not old news in my book. It wasn’t expected (or was it?) so sensible to ask the question what could be going on?

“a three- to fivefold accumulation of the active drug within the stroma compared with the malignant epithelium.”

“the antitumor efficacy may be due to direct cytotoxic effects on the FAP-expressing population (CAFs), a bystander effect targeting the vasculature and epithelial cells,”

Always good to recognise where the platform is managing to reproduce the observations made in the past by others but with the advantage of being able to exploit that knowledge by having human trial data rather than guessing from animal models.

No doubt Avacta will have seen similar in their preclinical work, would have been looking for evidence to build on what they think is happening in the stroma (obviously you think you know the mechanisms in play already).

We now wait to see if the observations/learning are somehow incorporated into the design of one or more of the new pipeline drugs.

I guessed at Paul Loadman and Matrix Metalloproteinases but whatever we get I reckon there potentially could be links to the mechanisms in play in the stroma itself.

Part 3

They said “Future studies will be directed toward further optimization of this prodrug approach and exploring the effectiveness of a FAP-activated prodrug in combination with other therapeutic modalities, including chemotherapy, radiation, and immune-based therapies.”

Look at what has finally turned up a decade later. AVA6000!

Incredible!

Part 2

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

I’ve given the interesting bits below but please read the discussion section if you can.

One advantage of this FAP-activated prodrug strategy is that it should have a therapeutic benefit independent of FAP’s role in tumor pathophysiology because it relies only upon FAP’s presence and unique post-prolyl endopeptidase activity to selectively activate a prodrug in the tumor microenvironment. FAP is a membrane-bound protease whose catalytic site has access to the peritumoral fluid of the tumor microenvironment where it can activate the prodrug. This extracellular activation results in the death of CAFs but also produces a bystander effect as demonstrated by the death of pericytes and endothelial cells within these xenografts.

Finally, the selection of a thapsigargin analog as the cytotoxic “payload” is equally important for the success of the strategy because this highly lipophilic agent, upon release from the peptide, rapidly accumulates within nonproliferating stromal cells and induces cell-cycle independent apoptosis. (Is AVA6000 allowing DOX to do the same).

……tumors treated with a FAP-activated prodrug show stromal-selective cell death and a bystander effect on pericytes and endothelial cells in areas adjacent to FAP expression. Moreover, fractionation of prodrug-treated tumors into epithelial and stromal populations reveals a three- to fivefold accumulation of the active drug within the stroma compared with the malignant epithelium.

The mechanism underlying this antitumor effect is not known and currently under study. However, the antitumor efficacy may be due to direct cytotoxic effects on the FAP-expressing population (CAFs), a bystander effect targeting the vasculature and epithelial cells, or a combination of effects on primary and secondary targets.

Additionally, uptake of the TG analog can profoundly alter protein expression and therefore may affect release of growth and survival signals.

Additionally, elimination of FAP-positive stromal cells significantly augmented tumor immunogenicity and regression of murine pancreatic xenografts in mice previously immunized with a mesothelin peptide. Although this immune-based mechanism does not explain the antitumor effect we observed because our xenograft experiments were performed in immunocompromised mice that lack T-cell function, it does suggest that combining the FAP prodrug with a vaccine strategy may warrant testing.

In conclusion, these studies validate FAP as a promising target for activating a systemically delivered cytotoxic prodrug within the tumor microenvironment. This study provides evidence that targeting cells within the tumor stroma, independent of the cancer cells themselves, could be a viable strategy for cancer management.