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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.

Unfortunately, Leukaemia doesn't appear on the high FAPalpha chart that has appeared in several Avacta presentations. On the other hand, a quick google search leads to a number of scientific papers on FAP alpha in acute myeloid leukemia. So perhaps it may be possible.

Also, it appears to dox is used to treat leukemia in some cases.

Yep (or at least very similar). This is why Avacta have stated that if AVA6K works in the clinic, it will open up a whole pipeline of Precision drugs.

Like many on here, I suspect, I had to do a bit of googling this morning to find out about PD-L1 inhibitors. Here is a good starting place: https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/immunotherapy/immune-checkpoint-inhibitors.html

Basically, the method uses monoclonal antibodies to switch off (or turn on) a check-point in order to trigger an immune response. It does this by binding to a protein on the surface of a T-cell. Essentially, it triggers your body's immune response to attack cancer cells.

As with all cancer therapies, there are some pretty bad side effects and limitations to the treatment. However, I can't find info on why these occur, i.e., is it due to the low specificity of the antibodies. Does anyone know more about this? How will affimers (smaller and more specific) improve the treatment?

Boom, thanks Wiggly!

And thanks to Tom for posting clips of AS, NB, and FMcL discussing the expectations before the trial began and what the expectations/drivers are as it progresses.

Given today's excellent news regarding the further dose escalation, I thought it would be worth while to step back and look where things stand. In order to be successful, ava6k must be 1) safe (at least relative to standard chemo), 2) effective and 3) must bring dox to the TME and be cleaved by the FAPa present (i.e., the Precision mechanism must work).

From the comments here today (and over the past few months), I think it is pretty well accepted that the safety and tolerability profile of ava6k is (very) good. The comment by Neil Bell today is very telling, that the dose escalation "is an endorsement of the emerging safety and tolerability profile in the patients enrolled in this study to date." The fact that the SDMC are happy to double the amount of ava6k given to patients, compared to the first dose, clearly shows the relative safety of the drug. So that's point 1 down.

We also know, based on 40+ years of dox use in cancer patients, that once ava6k cleaves, and dox is released, it is a highly effective drug. This is the major benefit of a pro-drug, this big hurdle comes pre-cleared. So that's point 2 down.

The question then is whether ava6k is cleaving in the TME (and to what extent), i.e., is the Precision technology opperating as seen in the animal models (and as we saw in the April presentation, that data is pretty phenomenal). Neil Bell addressed this in the business update in June 2021 (before dosing began), available on the avacta webpage. There he states (48:45) that in Q4 2021, i.e., in the early stages of the ava6k study, Avacta will have the data to "confirm the mechanism of action of ava6k" and "confirm that the results of the pre-clinal trials translates into humans". This wasn't a throw away statement, rather it was in response to the question of when the next Precision drug would be selected for pre-clinical (IND enabling) studies. His point was that the next drug wouldn't be selected until the mechanism of action was confirmed.

As we know, the second precision drug, ava3396, was selected and moved into pre-clinical studies in Q1 2022, thereby seemingly confirming the mechanism of action. While a big event, it didn't generate the excitment that some (i.e., me) expected. The doubt at the time seemed to focus on safety, was the specificity of ava6k high enough in the TME, or was it being cleaved throughout the body? I think that there was also concern at the time about the situations with dose escalation. These doubts have now been addressed. Hence, it seems to me that point 3 has then been addressed as well.

It will be interesting to see the market reaction to this in the lead up to the data (summary) being released in Q3 or Q4 this year. Will more people be joining the dots, resulting in a steady climb, or will the market remain skeptical with a "we won't know until an official RNS" attitude?

Sorry Sujood, it is not us and there was no mention of Avacta on the Radio5 live programme at the Christie today.