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We knew that rodents had higher FAPa levels, but at least I didn't know that it was a factor of 15! (note that the 'higher levels' quoted by Marty McFly was for baboons)

This directly feeds in to 'multiplicative factor' that has been previously discussed, i.e., how much more dox gets to the tumor than standard tissue. In mice it was 18 to 1 (tumour to heart ratio). With 15x less FAPa activity in humans than mice this has the potential to go to astronomical levls, i.e., if everything is linear (which I am sure it isn't, so this is just an example) this could in principle get to 18 * 15 = 270, so 270 to 1 (tumor to heart ratio).

Of course there are two ways for dox to get into the system with AVA6k, either through encountering 'systemtic' FAPa, or through leakage from the TME. I'm not an expert, but based on 1) the very rapid uptake of dox by tissue discussed by Ophidian (suggesting very low leakage levels) and 2) the fact that William Bachovchin's group is looking at the systemic variations of FAPa activitiy between species, leads me to believe that the major pathway of unwanted dox is through cleavage of ava6k from systemic FAPa. This suggests that this multiplicative factor could indeed be much higher for humans than for mice.

Can't wait for those biopsy results!

@Hurst10, seriously, please explain why you think that this is so interesting that you post it nearly every day.

@Hurst, could you please take 5 minutes and explain why you think BEGO (which I assume is one of the MMs of Avacta) is important (as opposed to the others), and hence why it should be brought to the attention of this BB on a regular basis?

I'm not being rude, or taking the p:ss. An explanation would be very appreciated.

Yeah, not to be trusted at all.
https://www.mcgill.ca/oss/article/covid-19-critical-thinking-health/dont-fall-vaers-scare-tactic

VAERS is a real system (although it is a 'voluntary reporting system', i.e., not based on the conclusions of medical professions), and can be very helpful. But it has also been seized by anti-vaxxers to misuse (misrepresent) the data/reality.

"Along with statements from political figures and far-right activists, we found a few websites which repackage data from the VAERS official website and misrepresent them to mislead people. One such website we identified was OpenVAERS. "
https://www.logically.ai/articles/double-check-how-does-openvaers-misrepresent-data

MrA, MTD is quite well defined, see here:
https://onlinelibrary.wiley.com/doi/abs/10.1002/9781118445112.stat07089

It is a statistical measure, where >33% of the patients display dose limiting toxicities. Hence, it takes into account that there will be deviations within the population. These are deviations beyond the obvious, i.e.., as Richob points out, that there are eligibility requirements to take part in the study. You're argument would apply to all chemo/HIV drugs, and yet MTD is still used in all such studies.

Once a drug is actually approved and in use, including chemo, the supervising docotrs will always look at the full health profile of the patient and adjust dosing accordingly. Hence, why you don't treat yourself with chemo. The more info available, the better.

Following on the discussion on twitter today about maximum tolerated
dosages (MTDs), a small update.

We've been told that (per unit weight) AVA6000 * 0.675 is equivalent
of dox (i.e., the first dose was 80 mg/m^2 of ava6k was equivalent to
54 mg/m^2 of standard dox).

We can go back to this classic Avacta graph, showing the ratio of dox
in the heart/tumor for standard dox and ava6k:
https://twitter.com/RAH00084/status/1552198161615175682/photo/1

MTD (in mice) of dox is 2 mg/kg. In the graph, this is compared to 12
mg/kg of AVA6K. Hence, there was 6x more ava6k given than dox. This
lead to 18x more dox in the tumor compared to the heart. From this we
concluded a while ago that there was a multiplicative factor of ~3
(effectively ava6k keeps going around the system until it finds a
tumor - see recent twitter threads by Ophidian on this), which should (in
addition to little or no side effects) boosts the efficacy of ava6k over standard dox.

However, in the graph, we see that it was 12 mg/kg of ava6k not of
dox. 12 mg/kg of ava6k is the equivalent of (12*0.65=) 7.8 mg/kg of
dox. So it wasn't 6x the dosage of dox, but rather (7.8 mg/kg / 2 mg/kg=) 3.9x the
dosage.

So 3.9x the dosage lead to 18x the concentration in the tumor vs. the
heart. So the multiplication factor is (18/3.9=) 4.6x!!! AS has stated
that there is less relative FAPalpha in the system of humans than in
mice, suggesting even less side effects, and an even higher
multiplicative factor for people.

Also, RAH has noted that MTDs are often well predicted by animal
models:
https://twitter.com/RAH00084/status/1552199302830759936
If 12 mg/kg was at/near the MTD (equivalent to 7.8 mg/kg of standard
dox) this is ~4x higher than the MTD of standard dox (~2 mg/kg). If
that is the case, then the current dosing of humans is likely to be
nowhere near MTD. This is likely why AS has mentioned many times that
it is possible that no MTD will be found.

Of course they could just keep upping the dose by ~40 mg/m^2 over
another 5 or 6 cohorts, which would lead to a 2+ year P1a study.
However, given the likely >4.6x boosting factor (and little to no side
effects), there is an urgency in moving the clinical trials along to
bring this to patients worldwide asap (assuming of course that it is
'working'). So on the one hand, you want to move to Phase 1b and 2
with the highest possible dose, but on the other, you want to move
things along as quickly as possible to benefit patients.

Thanks MrA, spot on. So we don't know the stage of the next Precision drug, but a whole new (Affimer based) pipeline is about to open up. I, for one, had not appreciated this additional 'iron in the fire'. Just when you think you've gotten your head around what Avacta are developing, a whole additional pipeline shows itself.

Just perusing the impressive Precision pipeline on Avacta's webpage and noticed that the next Precision drug (AVA028) has reached the end of the 'Research' phase, awaiting to move into 'Pre-clinical'. I'm not sure when this happened, looking back at the Annual Reports and other presentations, this Pipeline graph is only shown in the ARA2021 presentation (as it appears on their website). Can any of the sleuths track down when this change happened? i.e., have they continued to move drugs through the pipeline after AVA3996 was selected for Pre-clinical development?

The other noticeable property of AVA028 is that it is a PD-L1 Affimer® / IL2 bispecific, i.e., it includes an Affimer. Definitely a big step forward for the programme!

Great find gmcc! This deserves its own thread.

I doubt the pre-clinical studies are 'completed' (i.e., surely still in progress), but it is great to see some initial results. This really drives home the 'pipeline' aspect of Precision. If ava6k works in humans, as it did in mice, then we can directly read across to ava3996 and others. Fig. 3 appears to be even better than seen in ava6k pre-clinical studies!

I agree that the wording doesn't mean much, as it is just refering to the idea of the programme. It is excellent that the Therapeutics division continues to hire new (senior) staff, as I've argued previously, this division will live and die by the success of Precision, so expanding can only be seen as a very positive sign.

However, i'm intrigued by by the Affimer biotherapeutics. Is there anything known about using Affimers for therapeutics beyond TMAC?

Some ideas, in decreasing order of impact:
-release of the P1a results (i.e., "it works"), including biopsy data
-liscensing deal for ava3996
-formal/(real - i.e., industry) rumour interest from large biotech
-next Precision candidate announced with IND enabling phase
-Point annoucning "canseek" IND studies
-announcement of US hospitals coming online
-a diagnostic product for sale

But this is a good opportunity to highlight some of the benefits of ava6k. As we know, chemo has some pretty terrible side effects, which we can split into two types. The first type is temporary but can be devastating, this includes hair loss, nausea, weight loss, tiredness, etc. In fact these can be so bad that some people, after fighting cancer for 5, 10 or 20 years will actually stop treatment because they are tired of living with the effects of chemo. Obviously, removing these side effects would be a major result for ava6k. If you've known someone on chemo, you'll know how terrible it can be.

The second type is the permanent damage to the body due to the chemo. This includes cardiotoxicity, neural damage, etc. It is these side effects that can significantly shorten a persons lifespan, i.e., they can beat cancer but end up dying of e.g., a heart attack some time later, due to the damage in the heart. Even if you beat the cancer, you will (statistically) lose years of your life. If you remove these, you can keep dosing and dosing until the tumor(s) are gone, thereby increasing the surival rates on both the cancer front, but also on the side effects front.

You can see this in the statistics of the ava6k trial in mice. After 6 months, 100% of the mice that were untreated died. Also, 100% of the mice that got standard dox died. It was likely the dox itself that shortened the life expectancy of these mice (although we don't know how many died of the cancer or the side effects). But after 6 months 100% of the mice that received ava6k were still alive. So it beat the cancer and also did not shorten their life expectancy (at least not to within that 6 month window).

What Avacta are hoping to acheive wtih Precision is nothing short of revolutionary. If they reproduce the results from mice in man, we're talking Noble Prize level advancement (for our friend WIlliam Bachovchin).

Not sure where the author got their numbers from, but they are way off the official numbers.

For breast cancer, the 5 year survival rate (in the UK) is 85% (the author claims it is 1.4%)
https://www.cancerresearchuk.org/about-cancer/breast-cancer/survival

For lung cancer it is 22% (the author claims 2%)
https://www.cancer.net/cancer-types/lung-cancer-non-small-cell/statistics

For prostate (before metastasis) the survival rate is near 100% (the author claims 0%).
https://www.cancer.net/cancer-types/prostate-cancer/statistics

It's clear the author has an agenda that they are pushing, and the argument is not based on facts. That said, lifestyle changes and/or environmental changes can indeed have a strong impact on cancer rates. But chemo and other therapies are in fact very effective.

Nice one Richob. I've just gone over the AGM update slides again (from June 22nd), and note that on the first slide with info (slide 4, i.e., not just title slides) the first thing noted is "Focus on preCISION platform as the major near-term value driver" and a few points down: "ALS-6000-001 progressing very well". Avacta management continue to hold ava6k (and Precision more broadly) up as their major focus. Rather than temper shareholder expectations they continue to build them up.

While it is part of the boards'/CEO's job to provide a positive spin to shareholders, it would be suicide to draw attention (and build expectations) to an event (i.e., data readout) that is so close in the future. If things were going badly, or even just not as well as expected, I argue that they would be looking to deflect attention to other products or future events and temper expectations for the data readout.

They also mention that another hospital (the Freeman in Newcastle) is now online and recruiting patients. Like others I am a bit surprised that we haven't seen at least a small steady rise as news draws closer. My guess is that once/if the US cites are announced as 'online and recruiting' we might see a new wave of confidence amongst investors and we'll start to see that steady rise into the results.

All the above is only relevant due to the fact that Avacta are seeing the results in real time. This isn't just 'hope' or based on the previous (pre-clinical) studies. This is what makes things entirely different from the likes of Synairgen, whose double blinded (placebo-controlled) study meant the the final results were a surprise to all, including the doctors and the company.

Yeah, he corrects it back to Phase 1 later, but that's not a good start...

@Sparticus, if we could do that, why not just inject straight dox?

@MrA:

In response to your question, Why are people after major surgery and pregnant/breastfeeding women excluded from the trial? It's pretty straightforward, you would never give a pregnant/breastfeeding woman an experimental drug, as it could make its way into the baby. Note that even straight dox is generally not given to such women for this reason. As for the major surgery, this is because the body is heavily affected by surgery and the immune system is often severely compromised. This is not the kind of person that would be representative of the overall population, hence not a good test subject.

That's a valid question PL. Of course, from the point of view of the
trial, it is irrelevant where the patients are dosed. But I think it
matters from the market's perspective. Adding additional hospitals to
the trial at this stage is surely a positive sign, it shows a
willingness of the committee to expand the study. And the US is particularly
noteworthy, at least in the market psychology, in that it is openning
up a much larger potential market, with bigger players. This would be
a clear step towards US approval (eventually). Adding
international sites at this stage would seem ludicrous if the data to
date on ava6k wasn't living up to expectations.

In the AGM notes it states "Two US clinical trial sites being initiated and should
contribute to the dose escalation phase." So any day now, I would think.

My view is that this will be RNS'd and may be the start of the wider market taking note of the trail and potential here.

Is the new "Director, Business Development and Alliance Management" in addition to the Paralegal for the Therapeutics division that Avacta advertised a few months ago?

Definitely a good sign that Therapeutics is adding staff...