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Seems most likely Avacta (FDA) ran cohort 1 sequentially to mitigate any unanticipated safety risks. It is likely that the first patient in cohort 1 was dosed and continued until the 8 week surveillance. Then patient 2 was given the go ahead eventually followed by patient 3.

“Patients can be dosed in parallel in the two-weekly dose escalation study”

This means the first 3 patients in cohort 2 will be dosed in parallel so dosing will not be staggered as in cohort 1 unless problems with recruitment.

Well FM and NB the two persons responsible for pushing forward the development of AVA3996 have gone so we can’t ask them. Just a coincidence? I’m sure their salaries will help pay for a bunch of fresh, eager and talented PhD’s to join CC’s team and take forward the pipeline at pace.

An interesting thought; though not entirely original!

As I said before I’m convinced SB has catalysed a change of strategy. Reckon up to Dec 2023 the BoD were willing to give away 3996 much too early and far too cheaply. They now want to retain it for as long as necessary to realise its true value. As a minimum will probably hold until it’s well into P1 by which time the pathfinder AVA6000 will have cemented its own value and highlighted the potential for 3996 to follow in its footsteps but with greater impact.

“Ambition to retain 100% ownership of its pre|CISION™ platform looks likely to be realised”.

Introduction of AVA6000 to market before the end of 2026. Like many here I think it will be sooner via one of the FDA’s expedited programmes hence Avacta keeping things sweet with the FDA.

“Subsequent multiple licensing and partnerships deals with international pharmaceutical groups that can be expected ****to follow**** this successful commercialisation of AVA6000”.

Completing investigational new drug (‘IND’) enabling studies, submitting an IND/clinical trial application and initiating a Phase 1a dose escalation study for AVA3996 in 1H25. Sorry Takeda we’re keeping a tight hold on this one for now!

Next pre|CISION clinical candidate selected 1Q25.

TMAC clinical candidate selected 2H25.

SB probably looking to focus on deals for P3 partners. Hope he’s allowed to make an appearance at the AGM and take questions.

Couple all the above with the confidence to now pitch the pre|CISION™ platform as a serious player in the drug conjugate market. Avacta want to compete against ADC’c, other PDC’s, SMDC’s etc making it crystal clear they have dramatically raised their ambitions and want to be taken seriously. Yes! AACR is a jolly but it’s also the venue where reputations rise and fall! What do you think our Dr Udai Banerji might say to someone like Dr. Toshinori Agatsuma, Head of Oncology Research at Daiichi Sankyo, who believes ADC’s are the future of medicine. No! He’s not going to say it’s just a marketing ploy! He’ll put forward his respected views on what he believes possible given the encouraging data. My hope is it will be just enough to suggest that the pre|CISION™ platform is a lot more than reinvented chemo. Potentially a formidable competitor to these other approaches. My point being conversations will be serious and credible.

Hopefully, come the start of 2026, we’ll have witnessed a complete transformation!

It’s all down to the FDA’s new guidance on expansion cohorts (project Optimus).

In the original study we had phase 1a (dose escalation) to be followed by phase 1b (dose expansion) after which Avacta would define the recommended phase 2 dose (RP2D) and proceed to phase 2.

NOTE: Dose expansion BEFORE definition of RP2D.

In the new design we only have phase 1a study (3W followed by 2W) which will provide the recommended phase 2 dose (RP2D). Dose expansion has been moved into phase 2 to be followed by phase 2 efficacy.

NOTE dose expansion AFTER definition of RP2D,

FDA guidance

“The concept is straightforward: Once the recommended Phase 2 dose is determined in the dose escalation part of the trial, expansion cohorts can be opened to investigate different aspects of the oncology drug’s activity.”

“The use of expansion cohorts in first-in-human clinical trials can improve the efficiency of clinical development of oncology drug products, and this strategy has already been successfully executed to support the approval of numerous cancer therapies. Although these trials are complicated and have many moving parts, with appropriate planning and early interaction with FDA, this approach represents a feasible, expedited alternative to traditional separate Phase 1 and 2 trials.”

All very straightforward really!

An explainer

https://www.clinicalleader.com/doc/fda-issues-guidance-on-expansion-cohorts-in-clinical-trials-of-oncology-drugs-0001

Can you believe it, a bunch of randoms asking you to believe Dr Udai Banerj is flying 5000+ miles to stand in front of a poster display and tell 20,000 attendees that the data has all been fudged and Avacta have hit a rate limiting step but they’re working on fixing it. Better still, he’s going to try pulling the wool over the eyes of a highly intelligent audience and spin them a good yarn on why the trial failed to reach an MTD. While he’s at it he’ll trash the reputation of the FDA, the SDMC and the rest of the science and clinal teams delivering AVA6000 to many brave altruistic patients. For a laugh he’ll take the mickey out of the pioneering duo FM, NB who jumped ship because they knew better! As a finale he’ll refuse to answer questions without his tormentor being present. He’ll claim he was just an innocent member of the orchestra being conducted by the evil AS.

Wow! That’s sounds so believable!

This what Avacta have told us thus far

“All tumours that over-express FAP are potentially suitable for pre|CISION targeting. There are numerous cancer indications with a high level of over expression of FAP compared with background. What we do not yet know, which we will learn over time, is how high the overexpression over the background level in healthy tissue needs to be to provide an ideal therapeutic window”. (that time maybe approaching with the completion of C7 but, this data could be too valuable to divulge at this point in time)

“We have designed a very data rich Phase 1 study that will measure a number of exploratory biomarkers. These data will be presented in 2024 when new intellectual property has been protected”. (Are these biomarkers linked to levels of FAP expression?). Interestingly, very recent studies have shown that FAP activity can be quantified non-invasively (in serum) by the biomarker C3F using C3F ELISA assay.

https://www.mdpi.com/2227-9059/12/3/545#:~:text=FAP%20activity%20can%20be%20quantified,associated%20with%20high%20disease%20activity.

Regarding gaining new insights into FAP, Avacta stated “This is an important question. We are exploring this but these insights potentially constitute new IP which we need to protect before we can discuss them publicly. We look forward to discussing this in the future”. (Latest Avacta GB patent application 12/12/2023 methods for the treatment of tumours could it be relevant?).

Remember, a key clinical observation for 59-year old male with UPS stated “Correlative studies demonstrate high FAP expression in the tumour tissue”.

Clearly Avacta are finding ways to determine the levels of FAP in the tumour tissue. Is it via use of a bio marker or from analysis of biopsy tissue samples?

Whilst it’s accepted that FAP is over expressed in many solid tumour types, Avacta are also aware that methods to quantify FAP expression have no standard to follow and so quantification studies lack comparability. Not an ideal situation for BP if you’re contemplating committing yourself to investing in the precision platform where cleavage of your drug warhead depends entirely on levels of FAP expression.

Avacta are keeping a tight hold on data relating to levels of FAP expression and the correlations being observed. Why? Because alongside efficacy the FAP related data combined with PK/PD will leverage platform value. But could such data be a double edged sword. Greatly underpins and gives value to Avacta’s IP but when made public also gives something away to others who are also pursuing FAP as a target using similar conjugate drugs. These folks are about to go into the clinic.

https://www.philochem.ch/pipeline/oncofap-gp-mmae/

I can’t help but think Avacta have to play their FAP hand very carefully indeed.

Knowledge (of FAP) is power!

Is FAP the “right target”? That’s the million dollar question for BP when thinking about selecting the pre|CISION platform for delivering their warhead.

FAP has been recognized as a potential therapeutic cancer target for decades but for some reason BP largely ignored it. Even the recent surge in interest has only focused on its potential as a target for imaging diagnostics and targeted radioligand therapy. Of course Novartis (3BP/Clovis) have already dipped their toe in the water and we know about EL/Point and Sofie’s FAPI development. This has led to FAP being viewed as the next billion dollar theranostics target.

However, successful exploitation of FAP as a target outside of nuclear theranostics has been limited in terms of impact in the clinic. Avacta have picked up the gauntlet with their platform innovations but they have to take the fight to BP. Proving the platform works (AVA6000 efficacy) isn’t enough, proving the advantages of FAP as the “right target” for BP is also needed. For example AZN corporate strategy dictates use of their 5R framework which means target first; right target, right patient, right tissue, right safety, right commercial potential. So it could be: Choose FAP! Choose pre|CISION!

The performance of pre|CISION is totally reliant on leveraging FAP to target the tumour. However FAP distribution can be heterogeneous and the level of FAP expression critically affects the therapeutic window. Consequently there will be considerable focus by BP on what Avacta are learning about the levels and behaviour of FAP in the tumour/stroma.

Not surprisingly Avacta have been especially vague when answering questions relating to FAP.

Avacta are fighting hard to change perception. They want and need to be seen as a genuine “clinical-stage pioneer of next-generation cancer therapies” rather than a cash strapped wannabe with a one hit wonder to revive an old chemo therapy.

This is what the messaging is all about and it needs to be done carefully but quickly. It has to pitch the right messages to the right audiences at the right time.

We all know Avacta’s various platforms and pipeline products are about a lot more than just its next generation chemo. Here’s an example of Avacta being pidgeon holed with Chemo revival based on AVA6000 rather than where the REAL POTENTIAL of its pre|CISION platform lies.

https://www.alacrita.com/hubfs/Next%20Generation%20Chemotherapy%20-%20Life%20in%20the%20Old%20Dog%20Yet%20-%20Alacrita.pdf

You should notice AVA6000 being seen as a PRODRUG rather than a DRUG CONJUGATE. That’s a BIG PROBLEM for Avacta.

Well, what do you notice about Avacta’s poster? Oh look AVA6000 isn’t a prodrug anymore it’s a PEPTIDE DRUG CONJUGATE (PDC).

Why? Because prodrug only speaks of a one-off but PDC speaks of a groundbreaking platform.

Better still PDC’s (AVA6000 is an example) offer “A new paradigm for targeted cancer therapy” These are not Avacta’s words it’s how BP sees it. So don’t tell the audience what they already know!

https://www.sciencedirect.com/science/article/abs/pii/S0223523423010863

It is absolutely imperative that Avacta’s pre|CISION platform is seen to be a part of the the new era of targeted therapeutics which is all about drug conjugates and there are many kinds. Avacta will have to “compete” in this field. It won’t be easy but the advantages of the pre|CISION platform are already starting to show.

People don’t seem understand what Avacta’s “paradigm shift” refers to.

“a fundamental change in approach or underlying assumptions.”

“an important change that happens when the usual way of thinking about or doing something is replaced by a new and different way.”

“a fundamental change in the basic concepts and experimental practices of a scientific discipline.”

“a major change in the worldview, concepts, and practices of how something works or is accomplished”.

Avacta’s PLATFORM is offering a novel approach for SAFELY delivering large amounts of a highly potent cytotoxic agent to the tumour site. That can include those agents that have never been administered systemically for safety reasons. Thus far Avacta have proven the concept “the platform works” by delivering high amounts of active payload (DOX) selectively at the tumor site simultaneously reducing drug toxicity and increasing tolerability. As the P2 efficacy data emerges it will confirm that the platform offers a powerful combination of efficient killing and precise targeting. You could certainly argue that ADC’s haven’t been completely successful in this respect. Avacta’s data challenges the view of many that it couldn’t be done. “Many have tried and failed.” However, what is more important is it will usher in fundamental change by offering an awful lot more than just “chemo without side effects” for FAP rich tumours.

It is a “paradigm shift”

BUT you don’t tell the audience what they already know!

Most likely

Phase 2 studies are sometimes divided into phase 2A and 2B. There are no formal definitions of these divisions, but phase 2A studies are typically more preliminary and can address issues such as dosing and safety, while phase 2B studies are generally 'mini-phase 3' studies that provide data on efficacy.

AS taking a lot of the blame but we’re supposed to have an experienced BoD. Caught with trousers down basically ie not prepared for certain outcomes and now embarrassed by their inability to respond.

Q&A session IMC 13/12/23

“There is potential to partner AVA3996 or any other undisclosed pipeline assets at a preclinical stage. More importantly in the ***SHORT TERM***is the potential to ***PARTNER***the pre|CISION platform. This means potentially licensing the platform to a third party to use in combination with their own cytotoxic agent. Such a licensing deal would be expected to be narrowly focused on a specific agent or agents. The clinical data published on December 13th 2023 plays a pivotal role in generating business development discussions and ***ACCELERATING THOSE THAT ARE ONGOING***.”

“Please note: The Company cannot answer specific questions asking when or how it will raise further capital. Avacta has a number of options to finance the next key milestones (AVA6000 phase 2; AVA3996 IND; pre|CISION and Affimer pipelines to generate next clinical development candidates). There are dilutive and non-dilutive ways in which the Company can secure the capital required and ***THIS IS OF THE HIGHEST PRIORITY FOR THE BOARD***.”

Given these statements from Avacta in answer to shareholder questions only just a few months ago I can only conclude that the arrival and input of Simon Bennett blew apart the strategy of AS and the BoD. Could be lots of reasons obviously. Maybe SB pointing out that Avacta were under selling the platform and giving away too much too soon etc. Maybe SB was meant to conclude a deal but created terms that couldn’t be agreed and the prospect backed away. I’d even question whether AS and the BoD were of one mind on this? Whatever the reason for what amounts to backtracking I’m totally convinced SB was the catalyst for whatever changed.

Avacta science will prevail unlike the CEO whose goose is cooked!

Nice try but way off the mark!

Paradigm shift is all about the future and has always referred to the pre|CISION platform as a whole and what will emerge when pre|CISION combines with much more powerful cytotoxics. The rns passage you quote is solely focused on what AVA6000 can achieve for obvious reasons.

“AVA6000 has the potential to compete effectively against other approaches that limit the incidence and severity of doxorubicin related toxicities”

Being told AVA6000 will take on ALL dox based formulations not just bog standard DOX. So it will potentially displace treatments like liposomal DOX (doxil) and the various DOX combo treatments that aim to reduce DOX cardio toxicity.

Strategy one get AVA6000 approved to take on the complete DOX market. Strategy two create paradigm shift by licensing pre|CISION which facilitates the use of more powerful cytotoxics.

What’s not to understand?

Total of 650 trades, just one solitary trade at £80k, a few around £20-30k but 95% trades coming in below £15k. Says it all! Well coordinated attack? Yes! The trader gangs controlling the pocket money brigade. A few well timed sells and a whole bunch of lemmings went over the cliff! Poor sods!

The AIM game; oh what fun!

Ran out of characters!

https://www.tandfonline.com/doi/full/10.1080/19420862.2023.2229101

Look at figure 3 and figure 7. It tells you all you need to know.

Roughly 30% discontinued following clinical testing.

Less than 5% reaching FDA approval.

“Utilization of very potent payloads, however, limited the biologic doses that could be administered, often resulting in suboptimal payload delivery to tumors with lower target antigen densities”.

Bring on the pre|CISION platform.

Merry Christmas

Final brain dump

Not surprisingly many are drawing parallels and making comparisons with ADCs when looking at the pre|CISION platform. ADCs follow the same concept of delivering a potent drug payload directly to the site of the tumour for maximum effect with minimal damage to healthy cells. ADCs are being regarded as “hot property” with 100+ companies involved and 100+ ADCs in clinical development. But, with nearly 100 ADC products discontinued, it’s clear that for ADCs the targeted concept has proved difficult to translate into clinical success.

This is what signals the massive opportunity for Avacta’s pre|CISION platform.

The emergence of ADCs was also hailed as a paradigm shift in targeted cancer therapy but two decades on and the clinical evidence reveals limitations still exist, notably narrow therapeutic windows, unique toxicity profiles, poor tumour penetration and development of therapeutic resistance! Potentially all these limitations can be overcome by using the pre|CISION platform for targeting FAP rich tumours. We have to assume BP will want to be absolutely sure they can fully harness the potential improvements in safety, tolerability and efficacy offered by the pre|CISION platform with no limitations.

This is why BP will focus down on Avacta’s pre|CISION platform.

Remember, just like AVA6000, ADCs were also developed to expand the therapeutic index of standard chemotherapies and increase the therapeutic window of a drug. However, behind all the hype and optimism that surrounds ADCs the clinical evidence suggests that current ADCs don’t significantly increase MTDs of their conjugated drugs after all and systemic toxicity remains a real problem. Many ADCs have failed during clinical development due to their unacceptable toxicity profiles. Leaving many potent cytotoxic agents looking for a delivery mechanism!

This will feed the demand for Avacta’s pre|CISION platform.

It’s easy to understand how BP past experience of targeted therapies like ADCs could feed a reluctance to jump in too early but mounting evidence of the ability for pre|CISION to greatly improve safe circulation, prevent off-target cytotoxicity, and widen the therapeutic window that currently limits the clinical utility of many highly potent chemo agents WILL generate FOMO.

This is when the potential competitive advantages of Avacta’s pre|CISION platform start to sink in.

The above undoubtedly focuses the mind of BP. They’ll be extremely interested in the AVA6000 data but very cautious in its interpretation and translation to their own cytotoxic warheads. It’s unlikely that any BP would commit to a license deal prior to completion of the bi-weekly study. AS is well aware of what data BP want to see. Indeed, knowing this and with MTD not reached, the focus will swing to P1 ARM2 where the data generated will be “game changing” in cementing all the above.

BP will have to acknowledge that Avacta’s pre|CISION platform offers them

Not talking about BP reaction to Avacta’s preliminary data but shareholders response when AS revealed that the 10yo generic chemo drugs he’s been plugging in past presentations were now less likely candidates for the pre|CISION platform.

The pivot was clear “Fundamentally the way to maximise shareholder value is to develop the most effective anti-cancer therapies possible using pre|CISION. They would be the most clinically valuable and therefore the most commercially valuable. There are numerous more potent modern cytotoxics that could never be given as systemic chemotherapies because of their toxicities but they could be delivered potentially as pre|CISION chemotherapies. We believe it makes a lot more sense to select the most potent and effective cytotoxics rather than simply go down a list of old generic chemotherapies.”

He continued in the Vox interview highlighting the need to accelerate the pace at which pre|CISION drugs get to patients, “can’t do it all ourselves, need to get pre|CISION into the hands of other drug developers.” Then the emphasis came “the potential and INCREASING potential to partner the pre|CISION platform so others can develop targeted chemo using their own proprietary cytotoxins.” Avacta are pushing for pre|CISION drugs armed with highly potent payloads such as MMAE which is 100-1000 times more potent than dox.

If pre|CISION is going to transport these incredibly toxic payloads around the body for localised release only in the tumour then Avacta MUST provide the data that convinces BP that pre|CISION can achieve this safely with the levels of consistency and control required. Yesterday we had “These emerging data give us, for the first time, the opportunity to accelerate ongoing discussions….”

AS obviously knows this is very achievable and that’s not just because he has the clinical data from 7 cohorts. His remarks are signaling this is well down the track after a good few feasibility conversations with various BP who have experience of working with such toxins. AS would be embarrassing both himself and Avacta if he was pushing this without it having a really credible basis. Discussing the science, sharing the clinical data and building trust with BP are fundamental to Avacta’s progress in partnering the platform. That’s what’s being going on in the data room for some while.

A serious potential BP partner may even have influential input into Avacta’s “data” strategy as it drives forward with the AVA6000 trial. Once a BP is hooked it’s the only way Avacta can be sure of reeling them in. Continue collecting the key data needed to satisfy BP (polish up the PK/PD model), answer their searching questions and ultimately kill off any remaining scepticism or doubts that BP have regarding the capabilities of the the pre|CISION platform. (High FAP now please)!

We are well past “it works” but haven’t quite reached “let’s close the deal”.

More importantly Immix trial of IMX-110 for STS was very discretely dropped at the end of 2021 despite being granted ODD status and their mono therapy trial for solid tumors is not recruiting. They are only running IMX-110 in combination with tislelizumab (BeiGene / Novartis). Not a contender!

“Watch the price back above 160p with nothing left for the buyers.”

You’re going to nail it again Hurst! Love it! As always your genius shines through!

So many of the halfwits on here simply don’t get where you’re coming from. Presentation blah blah! ? As if you didn’t know that😂

Crack on, you’re a joy!

All too often the enormity of the statements or comments made by Avacta, AS ,FM, EF, Dr Tap etc regarding AVA6000 and the clinical trial data etc simply don’t sink in because the listener doesn’t have the knowledge or capacity to put the info into its true context and today is yet another example.

Avacta have abandoned plans for P1b to bring forward P2. What have they discovered in the P1a data that has caused this?

“Significant reduction in tumour volume confirmed in a patient with soft tissue sarcoma.”

Take a look at Table 1 in this paper. Take a long hard look! Let it sink in!

https://www.frontiersin.org/articles/10.3389/fphar.2023.1199292/full#T1

Dozens and dozens of studies going back nearly 40 YEARS.

There is A LOT of DATA for comparison.

MANY THOUSANDS of patients participated in the hope of a better outcome.

Even after all this time though, Dox or its combination treatments still don’t offer much hope! Outcomes barely improved. ORR 18%, 6 months PFS.

Then along comes Avacta with AVA6000

“we have a confirmed, significant response in a patient with soft tissue sarcoma”

That is a BIG DEAL!

At the top of the table we have Dr Tap who must of been incredibly disappointed at the end of his last P3 study trial.

https://jamanetwork.com/journals/jama/fullarticle/2764181

Imagine how he feels now, finding himself at the helm of the AVA6000 ship STS as it sails towards P2. So important to have him onboard given the sheer complexity of STS and the known heterogeneity associated with STS tumours. He’s the man who truly understands Dox and STS. It’s past, present and future and the significance of what’s now being achieved. Bet his confidence in achieving success with AVA6000 is sky high and he’ll be pushing Avacta forwards. Roll on P2!

Energyshares not sure you’ve understood the data

“Very interesting just 210.09 mg/m2 in the over-dose group.”

The figure 210.09mg/m2 is the standard deviation for the data; a measure of the variability.

The average cumulative doxorubicin dose was 714.38 ± 210.09 mg/m2 in the over-dose group. In other words around 68% of the 24 patients in the group received a dose ranging between 504.29mg/m2 and 924..47mg/m2

Look at the figure 2 data for the patients in the over-dose group; dose ranges from just over 300mg/m2 up to well over 1200mg/m2. Very inconsistent data probably due to small sample size.

Doesn’t change the conclusion though!