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Hanoi makes a very good point. We know efficacy of normal dox is dose dependent. We know the most effective doses cannot be used due to tolerability. Why are we surprised that Avacta seek to find an MTD if there is a possibility that new effects rather than larger effects are possible. These can then be reflected in design and doses of P1b study.

Can I make one prediction. Avacta will not be updating the market 60 days and one patient into a P1b clinical study. Indeed they are unlikely to update anyone until the trial and data analysis is complete. That's the way clinical studies work. Closest option to this would be safety and data monitoring committee stopping trial early because one or more groups were doing very much better than the others.

Been a bit disapointed in their efforts lately but this is great. Suspect something heard over a a quick shake at McDs and shared with Telegram self help group. To be fair it was good to see Richard write something that wasn't a straight forward fawn over his Lordship

Oh hang on. .

If AS is not careful then he will have to attend a performance improvement meeting with Myles just like last time.

Therapeutics Science Day 2023 – video recording

https://stream.brrmedia.co.uk/broadcast/63d3f8211874497653f33965

Have a look at this from 1.53 onwards. Actually look at guys whole presentation for the latest on the P1a study.

Talks about patients who would normally be unresponsive to dox being included.

Horses mouth

https://avacta.com/wp-content/uploads/2023/06/Avacta-Group-plc-Therapeutics-Non-confidential-BIO-June-23-www.avacta.com_.pdf

Study has been designed with both a clinically meaningful result and a statistically significant result in mind. The study patient numbers reflect these calculations. As mentioned AS unlikely start shouting from the rooftops based on low numbers. Indeed it would be irresponsible to do so. Given the disease area responses could vary within any one group and false negative be seen at very low numbers. Hence the need for more patients to create confidence in any result seen.

However, it could be a data surveillance board is appointed who will have on-going sight of the data. They could stop the trial early if they see a large enough difference - if conservative estimates have been used in the power calc then this is entirely possible.

Not sure they have been heavily treated previously with dox in P1a. This would count towards their life time exposure and I think the lead investigator also stated this at science day. Other reasons too.

I made up some numbers using a La Place transform and used a multiple variants of coefficient. It made me feel very clever but fell over when it was pointed out that it was built on using a naked dox dose and translating its systemic and therefore tumour concentrations over to ava6000. The slide 84 shows why that assumption is nonsense but you already know that.

It's like you take a spoonful of instant coffee and add it to a pint of hot water.

Then you take a spoonful + 25% more ground coffee and add it to one of those tiny little cups you get in Italy.

Guess which one taste stronger and wakes you up.

No beans were harmed in the making of this analogy.

Oh hang on....

310mg (C6) of ava6000 is likely to produce tumour levels much higher than 250mg of systemic dox. It is therefore not "equivilent".

310mg of ava6000 is unlkely to be converted to 250mg of dox. It doesn't need to since the volume of the tumour is small. I explained this to a six year old and they were able to understand it.

The equivilent argument undersells the unique way ava6000 acts in tumours whilst also keeping systemic exposure so low. We want the SP to go up and getting new investors to understand 310mg of ava6000 could be so much better than 250mg of systemic dox would help. We will know by how much when P1a data released.

Plenty of info on avacta website.

If it goes to another cohort or two then I believe this will mean the release of dox in tumour is higher again. There would be no point increasing the dose of ava6000 otherwise.

If it doesn't go I suspect its because the fap enzyme in tumour is saturated and the unconverted drug is eliminated before can work. We then go back to a slower dosing regimen ti maintain tumour levels whilst still keeping systemic cumulative exposure low. I think this will lean towards the high dose arm that's proposed in P1b. The other arm will try and match normal dox levels in tumour (see norm systemic Tmax) and have 18+ cycles.

I believe both arms will be superior to normal dox in terms of efficacy. Trial sets stage for Ava6000+ another drug since If tumour structure can be disrupted (see mouse photo) then other drugs cabn get in to do their thing. Avacta keeping both approaches on table which should inturn keep clinicians excited.

This time next year.....

The side effects associated with ava6000 are presumably associated with dox that is released either into the circulation from the tumour or systemic FAP.

The concentration of systemic dox in cohorts to date is well below those concentrations associates with normal dox. This concentration is used as a benchmark of benefit vs risk or tumour vs heart.

The proposed continue until mtd found is confusing given the low levels of dox seen and the SD claim that we are miles off MTD. It may be that they have lowered the threshold of an MTD below that seen with normal dox. This only makes sense if the corresponding "benefit" exceeds that seen with normal dox.

In terms of the rest of the pipeline it would seem odd to set an mtd for drugs which are not as toxic based on dox release. Maybe it supports starting pK studies at higher doses or bigger step ups. As someone else mentioned this may therefore be driven by potential partners wanting to derisk or at least be better informed.

Guessing how long this could take is a mugs game. If they see one patient withdrawn they enter three more and thus it could be prolonged. If they go to c6 and C7 patience will be required. Ramp squad will struggle but I confess to wanting us to get there. Stopped looking at car magazines now.

Perfect flag. Does it have a dragon on it in which case it is either Wales, Georgia or Bhutan.

Ava6000 mechanism of action is to convert an "inert" substance into active dox within the tumour environment. Due to the small volume of the tumour in comparison to the whole body then only a small amount needs to be converted to create a high concentration within the tumour.

Some of the dox created within the tumour may leak out into the systemic circulation but due the volume is diluted into A low concentration. See the tumour to blood ratio from SD

Comparing the mass of ava6000 that is administered to the mass of dox required to create a systemic concentration completely misunderstands the unique targeted delivery of ava6000 and its potential to hit tumours with doses that cannot be achieved with normal dox without damaging the heart. The conc of dox in tumour with ava6000 is more dependent on conversion than the equivalent amount of dox it represents on administration - it looks like its many times higher - that's a good thing.

Sometimes people get the right answer but their working out detracts from the jewel that targeted conversion represents and is the value driver for whole pipeline. Cannot blame market for mince impression if twitter bombarded with nonsense. Must try harder

If this initial approach works the the value of whoever holds the rights to affimers will rocket well beyond Affyxcell.

Oh hang on.......

Yep you are right.

Avacta have had the affimer licence for over 10 years.

I just find it odd that they don't highlight the dose in tumour is more a function of targeting a small volume high in fap than just administered dose. Ava6000 isn't raw dox and therefore the actual tumour dose is related to fap conversion - this is what created high levels of tumour dox. Maybe the PR jockey doesn't get it but given the concept is important to investor understanding I think its a missed opportunity.

Actually think the C5 et Al cohorts are more about finding the saturation point of FAP than MTD. I don't think it's possible to give ava6000 at doses that create systemic concentrations similar to normal dox - surely that's the benchmark in terms of tolerance.

Like the point you make.

IF Avacta have finally created one or more affimer based Dx then acquisition of distributors enables market penetration. Better to have this in place to sort stuff like regulatory which others have highlighted as an issue previously.

Perhaps Avacta don't want to tell us SH about current situation because of commercially sensitive. We are having to guess these gaps and funding going forwards but I confess to being nervous based on previous statements being 180o opposite to company activity. Share price reflects this for the moment

They mention Germany several times so it looks as if spending isn't over. If its buying market share instead of a delivery strategy as you suggest then it's expensive and probably less return than say developing a third precision product or even moving one of the affimer Tx forwards (has this been dropped). Logically therefore your proposed strategy makes sense.