Member Info for RorkesDrift

Are there any women here....

Waits for someone to bite.....

We are going down a dead alley but all, every, without exception enzyme reactions are able to be saturated.

From the bbc guide for children

"As the substrate (ava6000) concentration increases, the enzyme reaction (ava6000 - dox+leaving group) increases until all of the active sites are occupied by the substrate. When all active sites are occupied, the enzyme is saturated".

At this saturation point, adding more substrate makes no difference to the reaction rate.

What you are suggesting is that there is so much fap enzyme in the small volume of a tumour that there will always be active sites available to any passing dox. If this were the case then it is similar to first pass metabolismn with immediate conversion of ava6000 to dox.

We dont know the pK values so none of us can say what us happening. You could be right and 100% of ava6000 is converted to dox within tumour before any is eliminated. That doesnt change the fact and therefore the possibility that as doses of ava6000 increase the enzyme becomes saturated. This may be before or after mtd vs incressing biological activity is reached. The only people who have an inkling are those that have sight of the leaving group pK. The picture you paint is entirely possible but.....

Worth pointing out that if saturation is occuring then higher doses of an inert substrate like ava6000 would extend the duration of the pK curve something not possible with drugs that have a toxicity threshold. The alternative approach would be to give smaller doses, more frequently.

Oh hang on.....

Oh dear Hanoihank. Ive enjoyed your previous posts but think your account has been hacked.

I found this link which i think is written for 11-14 year olds.

https://www.bbc.co.uk/bitesize/guides/zm6j47h/revision/4

I found it by simply googling "enzyme saturation" which it turns out is a thing.

But you knew that

You say potatoe farmer, I say potatoe pharma

40p. No-ones mentioned a 5 to 1 share split or did i miss it

Avacta and affimers. Taking too long but we cannot have cake and eat it. Therapeutics is a better use of cash which is why Dx acquisition and market consolidation appeaers odd. AS implied diagnostic division was going to be key of agm. Im guessing the deal that fell through caused a pivot back to talking about therapeutics. Perhaps Dx market caps depressed so bought whilst Avacta can afford it. Now need to do something whi h justifies the opportunity cost of that capital.

I also chuckled at his slight p1zz take out of the more "enthusiastic" members of the Avacta share holder community. When you look at the facts its pretty cool but will take time. Chill.

Excellent question

"I asked FMcL that if the biopsies were taken at 24hours, and given that the level of dox found in those biopsies is already high enough to kill cancer cells, is it reasonable to assume that the peak dox levels in the tumor is substantially higher (i.e., given the half-life of the drug in the body, there would be more dox in the tumor after say 4 or 5 hours than at 24 hours). Her response was that was her expectation (but that it hadn't been measured).

Not sure. Rolling out a new drug is often phased for very good reasons. For example germany is often first to launch cause it high volume and high price. Then used as thebbench mark for other regulators. UK is often delayed cause we have additional hurdles - pricing and NICE being just two.

All products have an adoption curve - ava6000 might be fast but wont be overnight. Clinicians will adopt at different rates - reasonable given there will be a learning curve.

The most significant though will be market expansion. As clinicians become more familiar with a drug they begin to use it in different ways. New data will continually arrive and this will shift practice but new indications such as breast cancer would benefit from regulatory approval rather than what is in effect off label use otherwise.

Thanks JT - she seems a very straight and balanced person . My take on that is there are further benefits over standard dox with that approach. For example we see greater tumour shrinkage or the drug is even better tolerated. (Mouse photos). My understanding is dox stops tumour growth whilst its given but when it has to be stopped then brake comes off. Therefore treating for longer would be better if there is no additional benefit. Hence they are thinking ava6000 is even better than first thought.

However, im dubious about 12 months but fantastic if im wrong. Right pass me what car magazine again.

I meant to say that i think more frequent dosing within 18 weeks will be about greater efficacy thsn standard dix. See mouse photos

My belief is that the benchmark is to dox prevents the disease progressing and it does this within the standard dose and three week interval.

If ava6000 is aiming to show equivilence to this then it may be that more frequent dosing is necessary e.g.18 x weekly cycles. The implication tbough was that ava6000 could be given for longer hence keeping the tumour in check. Dox stops at 18 weeks whereas ava6000 continues for 54. This route would mesn it is 18-24months to get final PFS stats.

Both of the above are possible within same study - two arms. Im thinking more and more that avacta will build an interim analysis in which could then match AS timeline especially if recruitment is quick.

In terms of pharma deals it is standard to pay upfront for options to continue. Lots of deals have stopped when milestones not hit or the buyer has a change in priority. Option to stop with buyer. The deal with LG looks like this x sevetal compounds. So talk of cash in bank ignores future milestone payments from LG - ind approval will almist certainly be one.

The size of the payments are proportional to risk. Hence keep in house for now aoproach. My guess is son of velcade will go cheaper than we want this year but will have higher thsn 15 % of sales attached. Such a move would highlight precisiin to others - i expect a couple of deals to be announced q3 next year (after P1a).

Thanks for this. Great stuff.

Was good to see share holders being able to ask questions live yesterday.

I wasnt sure about some of the answers. One discussion revolved around P1b and the timelines. My calcs are that if it goes to 18 cycles then this is 54 weeks. Im thinking just the treatment phase for each patient is over a year. Have to top and tail that with patient recruitment and data analysis.

Options are for interim analysis but given primary efficacy variable is progression free survival and normal dox achieves this whilst its been given the timeline still looks optimistic. At the time point where one group has received ava6000 for 18 cycles and the other has had dox for 6 + 12off cycles would presumably show a bigger difference.

If ava6000 goes beyond dox and actually reverses the tumour then interim could yield a result. I am concious of the photos of mice tumours and reports of ava6000 providing benefits to some patients with tunours not normaly treated with dox.

The talks were very confident yesterday and gave a sense that current data is very good. Just not sure about timeline - i could have it wrong but several have been missed before and that just enables the knockers to jump in.

Dont touch the Shorts bread

Rich T

I suspect they have continued beyond 450mg on a compasionate use basis. The slides were presented at SD when the most any patient had received was 8 cycles. Two possibilities

1. Patient had received more than 8 cycles but 9 and beyond not included in trial dataset. This matches the data from comparison has well

2. Patient has had dose changed from every three weeks. Maybe they monitor with bloods and hit tumour when feel its required

So one patient has had at least 8 cycles after over a year of the trial running. The median was 2 cycles. Hence im a little bit dubious of the 24 cycles calculation. I find Occams razor handy.

Following my own advice im pleased for those human beings who have benefited and sad for those that didnt. As we move to higher doses maybe all patients treated will see some benefit. Lets hope so

The biggest problem with the 24 cycles of treatment is that avacta recently published information in their AE table - the one they boot strapped to data from the Announce study.

In this table they say the range of doses is 1 to 8 with the median being 2. I dont have a calculator but C1 dox nieive patients may be within the stated cummulative dose maximum stated in the trial protocol after 8 cycles

The table also shows a much improved tolerability against dox it isnt side effect free. By pausing treatment for 3 weeks the incidence and severity remains low.

Some (if not all) patients are responding to a treatment that is not normally used for their condition. That is amazing and offers a hope that Avacta will bring a new, effective and well tolerated therapy to even more patients. This will take time but once that hard evidence exists then as a wise man once said - ava6000 becomes the new standard over night

So current protocol is dose every three weeks. Im trying to work out the term "no dosing holiday" could mean.

Is this no holiday equivilent to a dose of ava6000 every week? Or every day. Or twice a day. Or a large loading dose with hourly top ups. Or a continual infusion delivered from a canister like a scuba outfit.

If there is no dosing holiday then rationale for the chosen posology will be part of the patient informed consent pack. No doubt will be huge part of the discission over pork pies and tea at the interval and im expecting follow up flyers, posters and a shumper wearing video conference at the very least.