Member Info for RorkesDrift

SD had some reassuring biopsy data and dox levels at 24hours. The tolerability is also very reassuring. On its own is a very good reason to continue to hold for me.

However, majority of the data (rich as it may be) remains under wraps. For example AuC of leaving group, the importance of which some understand. Dox may be dox but would be great to see how much - I'm hoping it is going to exceed the mouse conversion albeit not sure they will go up to systemic dox levels of normal dox.

I think they will hold fire on this until study completed for lots of reasons. Putting mtd into context, high impact journal etc. Therefore won't be revealed on Tuesday but hopefully in next few months.

Might have to buy subscription to what car at this rate though

If you think this is ramping..... :-)

Share price is currently 4% below where it was last year. Expect discussion of

1. Chemotherapy market worth £60% and growing at 10%+. Dox is standard of care across a large proportion of this. Peak sales across 3 tumour types could exceed $1.5B

2. Market is constrained by tolerability. Precision aims to go someway to solve this. Therefore efficacy, tolerability and revenue could all be associated

3. Avacta have exclusive licence

4. In mice model ava6000 produces a 18x difference in tumour and systemic exposure to dox. An even greater ratio has been seen in humans. Promise to update market with total exposure of tumour based on pK data at end of P1a. Update on P1b plans but no info on dose until P1a complete. Explanation why end date wasn't Q3 2022 as outlined previously - positive spin that higher doses possible.
Discussion of US involvement.

5. Ava6000 could significantly grow value of dox therapy due to more cycles x price premium

6. Long list of other potential drugs Inc. Ava3996. Possibly update on third product moving to preclinical and f/c date for Ava3996 going into human trials - IND later this year

7. Highlight velcade issues on tolerability yet value $1.2B annual sales. Limited to MM but opportunity to expand indication if tolerability is addressed.

9. TMAC program update. Warm feelings

10. Update of LG and Daewoong - positive progress on both.

11. Diagnostics. Is the new strategy working Inc financial

12. Given progress is represented by all the above then SP hasn't progressed with it. AS to give his take on this. Expect discussion of reflects dilution from raise but empathy with LTH which is nice.

How are the pump and dump team ever going to make their money if you pour cold water on something that has been in the diary ever since they did the same thing last year.

Toaster - It also says enrollment has begun....

For my next ramp .....

BV think you may well be right. I guess if 1b hasn't started then patient would receive standard of care if they were on a sort of waiting list. Randomisation and therefore study inclusion could wait until last minute has long as patient were aware that either could happen.

Whichever momentum seems to be increasing

Ava3669 should be inert and have limited effect on cells. Stromal cells presenting FAP cleave the molecule into a leaving group and an active "warhead".

Can you spot the right notes in the wrong order in the following

"For AVA3996, because the stroma cells are the ones expressing FAP to effect the pre|CISION cleavage, their presence enhances the impact of AVA3996. We can think of it as - to get past the filter the drug gets released so everything getting in has impact at killing cancer cells"

Lol. I'm filtered by most of the Telegram self help therapy group - shouted out "new biscuit, new biscuit" from the side lines too often.

Matml : From the rns

"Active enrolment has now begun for soft tissue sarcoma patients to the phase 1 clinical trial in the US, led by Dr William D. Tap, Chief of the Sarcoma Medical Oncology Service at MSK, and Dr Lee D. Cranmer, Professor at the Clinical Research Division of Fred Hutch Cancer Center."

I'm assuming enrollment is equivalent to recruitment but hey I may be mistaken.

As I say it infers ethics committee think it's acceptable to switch patients from current standard of care to Ava6000. They could only make such a decision by considering the data generated so far. Whilst any difference in either direction is unknown the possibility of an improvement must be significant or else the study wouldn't proceed. That's not to say its proven .....

So the STS patients won't be in C5. This matches the requirement that those patients have tumours that don't normally respond to dox - indeed are dox nieve. Hence P1a is about tolerability and safety not efficacy.

However, recruitment for P1b has started and thus ethics approval has been given. Start date cannot be that far away.

It may be possible for some patients to receive treatment to "test" protocol and data collection prior to trial patients starting. I've seen this for phaseIV studies but not sure if it's acceptable for unlicensed.

From the RNS

"The US trial sites will initially contribute patients to the dose escalation phase, while being uniquely positioned to lead the enrolment of soft tissue sarcoma patients in the phase 1b dose expansion stage of the AVA6000 study when this begins."

It looks like P1b is going to go ahead.

In order for this to happen ethics approval will have been given. Real patients are involved.

The ethics committee will have to conclude that patients in the trial drug arms have a realistic chance of an equal or better outcome than the current standard of care. Whilst a worse outcome is possible (It happens) the data from P1a would have to favour a better outcome. Add into this that there is a trebling of cycle numbers and the aim of increasing PFS to 18 months the initiation of first patient in P1b should esee an uplift in SP on basis that independent reviewers of all the data are positive about potential outcome. Not over the finishing line but clearing a major hurdle with the wind in their sales. (To mux my metafores)

It's a major part of P1a so they already know it for 20 patients. The numbers they are seeing has prompted them to talk about lower more frequent dosing and aiming to extend PFS from 6 months to 18months. The alternative of aiming for very high concentrations in tumour at cost of increasing AEs doesn't seem to be direction they are headed. This suggests that they are seeing similar or greater exposure of tumour to normal dox within first four cohorts - that's a guess but data available in next 3-6months.

I hope big pharma have asked to see data to date though.....

Literally everyone already knows dox is dox. Soon we will know exactly how much hits the tumour over time - I'm thinking this is the data that will reduce perceived risks

My assumption is it will be positive because
1. Mouse model particularly photo
2. Human values at 24 hours in C4
3. MHRA signed up to study extension
4. AS stating P1b will proceed even if DLT found in C5

Given there are about 270M shares and daily volume is about 2M your calculations on two day churn don't sound right?

Whilst "the market" is imperfect I'm not sure its worse than an individual stock picker. Both have access to the same info but one is an aggregate of 1000s of opinions which reduces bias and if wrong just creates an opportunity for you to rely on the other completely non- biased commentary and swap your house for Avacta shares. But you won't :-)

Initial impression was that he has over done the claims again - understandable given given how much he has personally invested. P1a is going very well and supports hypothesis but neither the regulators or the market consider it to be absolute proof. I really hope and now expect that to be provided over the next 12 months as Avacta move to measuring efficacy as well as safety. A stepping stone to this will be the pK data and a measure of tumour exposure to dox. On a related note AS twitched every time Paul thingy misused the term potency - MM now doing the same. Surprised the xspurt hasn't offered advice.

But...

Have to take my hat off to his insight on the potential to licence out the Precision tech rather than develop every compound themselves. Why develop a systemic product when clinicians will want to use a targeted product that achieves higher tumour concntrations and better tolerability. Precision offers product enhancement and extention of product life cycles - suspect avacta already being approached and could be a source of considerable revenue and contribution . Fair play to him.

Synairgen might arise from the ashes. They have a response - just didn't set it as their 1o efficacy variable.

Rumours down McDs is that their is possible a new government funded study that matches their product. Not sure you will get money back in short term but don't abandon all hope.

Biggest difference is Avacta isn't a binary play. Plus precision tech is improving existing therapeutics which are well established. Bring one home and we are laughing all the way to the new car show room

Why would it rose today. Much of the data presented already in public domain added to which it is animal data. Its all very positive and supportive of the opportunity many here see. However, it is not particularly new. Nice to see Avacta morning glory but that's just a warm fuzzy feeling.

The RNS that will prolong the rise will be significant and I think due this summer - P1a final report + partner + milestone.

In mean time I'm happy that the data is supportive from a scientific and clinical view. That's far more important than any helping hand from the market

Mice model was 4x dose resulting in 18x concentration in tumour compared to standard dose of dox. However 4x the dose also resulted in cardiac exposure so you wouldn't want to replicate in humans.

C4 was about 1.8x the weight of dox. You don't need to convert all of this to dox within the tumour to get very high tumour exposure. This reflects normal dox is distributed throughout body whilst ava6000 delivers it to the tumour.

To get same concentration as normal dox then a 1.8 dose would need less than 1% to convert.

Above this convetsion rate the tumour exposure is significant. Using mice model as an assumed straight line graph could imply c4 tumours are being exposed (auc) to dox far in excess of the headline 1.8x the normal dose. We will know by how much this summer but biopsy data (single data point) looks very promising. Additionally fap distribution in humans is different so the systemic exposure may remain low even when tumour fap is fully saturated.

The dose comparisons between dox and ava6000 are misplaced. What really counts is how much of an inert drug converts to active dox. No-one outside the company knows this.

The high levels of dox seen in tumour biopsy 24 hours after administration are very very positive news and shows Precision is working. Even better is these tumour concentrations dont require the high systemic levels of dox and subsequent cardio toxicity.

I think Avacta have already concluded that they are high enough that the worse case scenario is the c4 dose is enough for therapeutic benefit but also for far more cycles. This would extend PFS to 18 months (from 6 months). Thus have enough data that they know P1b will proceed and have received the nod from MHRA. The market will catch up once the P1a data is published. SP will respond like a hockey stick if expectations are met - the dox is dox becomes more meaningful to market at that point. Looking like avacta just need to optimise dosing over and above what looks great even with the simple P1a approach.

However, it could be that even higher tumour EXPOSURE could be achieved

1. By giving higher doses - so far the tumour concentrations are correlated to dose. Hence C5, etc
2. By giving same dose but over longer time frame - flattens the systemic pK of ava6000 and increases exposure of tumour to dox (see AuC of leaving group). Already alluded to for P1b.

Today's presentation filled some info in but market aware of most of it hence muted SP response. Publication of p1a pK data is soon - after that we and the market don't look back