Member Info for jive_turkey

You listed J&J, a global pharmaceutical company worth $430B with dozens of ongoing oncology trials, and you laugh that I guessed at the wrong drug that you meant? perhaps you actually list the drugs by name that you think could be competitors.

Ok, that's the old GPX-150 trial. So what? Is it a different drug? If not, the results still hold.

@RD, that assumes that the specific enzyme is 'used up' by a certain reaction, i.e., it is either destroyed or modified by the reaction (or that the substrate sticks to the enzyme for some time, thereby limiting access to the enzyme for other substrate molecules). For FAPa, this is not the case. FAPa cleaves the precision chemistry, which leaves FAPa in the same state it was previously, i.e., it can cleave another molecule with precision chemistry, and another, etc. I guess that in principle one could have so much ava6k in the system that every single FAPa enzyme is 'busy'. But ava6k isn't cleared rapidly, so ava6k would just keep circulating until it finds a free FAPa. This might slow down the amount of dox being cleaved a bit, but I would be surprised if this was the limiting factor. AS has stated the multi-cleaving ability of FAPa in a few presentations.

Also, he has stated that eventually the MTD will be reached, when enough dox is present in the blood stream, simply due to ava6k cleaving from FAPa that is freely circulating (i.e., non-tumor FAPa). FMcL confirmed at the AGM (over lunch) that they have a good idea where MTD is going to happen as they are measuring the amount of dox in the blood for each patient. At some point, you get as much dox in the blood from cleaved ava6k as you would with a standard dox dose (albeit with much more in the tumor). That will be the MTD. (unfortunately she didn't say when they were expecting to hit this limit).

Monopar : Camsirubicin - "The progression-free survival at 6 months was 38% which compared favorably with recent reports of doxorubicin's 6-month progression-free survival of 25%, 33%, and 23% in three separate studies in the same patient population." Very limited clinical improvement, although indeed cardiotox was reduced as well. Seems to have entered Phase 1 in 2017, so no one is definitely rushing to pick this one up. Other serious side effects still present.

Immix - IMX-110: This is a more interesting comparison. Not a platform, a sole drug, but one that could have some benefit across multiple cancer types. However, this is 1) a new drug and so has a long way to go to approval and 2) there are clearly some serious side effects, as P1a was just 2 patients and P1b is where the dose escalation will begin, and P2 is just 30 patients. This just goes to show how amazing our P1a/b trial design is. Clearly on an accelerated track.

For J&J, do you mean YONDELIS? That was approved in 2014. Clearly much to be improved upon (as dox is still the standard of care.

The above was very easy to find with a quick google search.

@ShearClass, unfortunately there are a lot of errors and misunderstandings in your post. First, C5 took 77 days, not 155. The first patient was dosed on April 5th and it finished on June 21st. The time between the completion of C4 and the start of C5 was due to Avacta needing regulatory permission to continue to higher doses than originally planned. This has all been discussed in RNSs and presentations.

Next, Avacta don't choose the dosing levels, that is up to the clinicians running the show. And if you think that a trial can/should increase doses regularly at 50% above the previous dose, you have a gross misunderstanding of how medical trials are run. So your question to management is not sensible. If you want to know why they started at 50% increase, then 33% then 25%, the answer is that they are following a standard 'modified fibonacci' sequence, typical of P1a trials.

@icecool, I don't know. They wouldn't go into detail into which patients had their tumor growth stopped (although they did mention two in the afternoon session - one with pancreatic and one with oesophageal, which was an unexpected announcement), what their histories were, etc. Just general comments about it and what can or cannot be read into it.

I was part of a group discussion with AS over lunch, where some people were pushing him over this (i.e., lack of tumor progression). He said that due to the fact that these patients are heavily pre-treated (multiple lines of previous treatment) that one can't assume that the lack of cancer progression is due to ava6k. And he emphasised that this was 'clinically speaking'. However, his tone and expressions clearly indicated that it was very likely due to ava6k, i.e., what are the chances that multiple patients would have their tumors stop growing when they started ava6k treatment. It's low, but not zero.

The patients in P1B will not be pre-treated, so this will be a direct measurement. But, in my opinion, they should have a very good view on progression in C5 and C6 at the higher doses. And with each new patient, the statistics improve.

I mentioned in my notes yesterday, a key finding of the trial so far, as emphasised by FMcL when I spoke to her, is the lack of Myelosuppression (the cause of Neutropenia, Anaemia, and Thrombocytopenia from the SD slide side effects) seen so far. This is the reason why dox is only given every 3 weeks, as the body needs to recover white blood cells (apparently, a very common side effect of dox is that people on it don't have enough platelets in their blood, so even with a small cut on their finger they need to go to the hospital as their bodies simply can't close the wound).

She made it clear that the P1b slide was just an example and that nothing had been decided yet. She was also pretty clear that the goal is more rapid dosings (every 1 or 2 weeks instead of 3). When asked if that would shorten P1B (i.e., you get to 18 cycles faster) she said "maybe, that's definitely a possibility", but that such trials are complex so nothing can be taken as a given.

Yes, I can confirm this.

Thanks ST, wish i could have stayed for the drinks!

-Results:

-only 3 out of 29 patients to date (c1-c5) have had myleosupression (specifically problems in the white blood cells). From the SD slides there were 2 in cohort 4, which implies 1 in c5. This is amazing, as with standard dox this would be expected to be at least 50% of the patients. This is what limits traditional dox therapy to once every 3 weeks (their white blood cell count has to be high enough).

-Andrew Saunders confirmed that the serious (grade 3 and above) side effects appear to be largely dose independent. Hence, higher doses don't lead to worse side effects (so far).

-My take away from the above and afternoon session is that they are still looking for the higher dose in P1b. And that so far, higher doses lead to better patient outcomes.

-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).

-And that the '7 years until astronomical evaluations' that I've seen referred to is (of course) taken out of context. The point was that 7 years from now, at 'peak sales', the evaluation would look very different than today.

-Quote of the day: a clinician on the trail said that they couldn't tell when a patient got dosed due to the lack of side effects. boom!

The AGM today was excellent, great presentations, Q&A and I'm particularly impressed at how much of Avacta's senior management was there and how open/available they were to questions and comments. I was able to speak to AS and FMcL over lunch and both were very approachable, although there were clearly some guidelines about what could or couldn't be discussed. And they put on a very impressive spread for lunch.

I learned a lot during the discussions, but the main one was just how 'dirty' chemotherapy and chemo trials are. The patients are very ill and are in and out of the hospital often, meaning that regular dosage is a luxary and that every patient is different. FMcL tried to put this in context by saying that in her experience, nearly all chemo patients will end up in the hospital at some point due to the treatment or complications of the disease.

Some points:

-First for RAH: no there have not been dosing holidays for the patients who remained on the trial. At least none due to ava6k. However, there may have been for other reasons (infections and antibiotics, illness due to previous treatments, etc).

-As Tom has posted, most likely the patients that remain on the trial are C3 and higher. The Avacta team didn't say this explicitly but it was implied in conversaion.

-The 450mg/m2 lifetime limit is not applicable in this trial. They have PK modellers which model data from the plasma to determine the 'effective dox' in the blood. So it is only when they get to the "effective" 450mg/m2 lifetime limit that they will stop dosing. It was implied that this was still some time away for C5.

-Something crazy: for P1B the straight dox arm will be made up of volunteers. i.e., people who choose straight dox over ava6k. Implied that US investigators are experienced in getting volunteers for the 'traditional treatment arm'.

-Something I was wrong about. 11 out of the 19 C1-C4 patients were colorectal cancer (CRC). I said that surely that can't be random. But AS told me that it was (and he was surprised by it).

-There have been 7 STS patients so far. From the presentation there was only 1 in C3, implying that they made up a large fraction in C5. The implication is that the US sites (STS dominant) are contributing heavily to C5 and above.

-Price: only £75k per patient in P1a.

(Results continued above/below)

@rambo, my guess is that it is just like in c1-c4 where they ended up with 6 patients in 3 of the cohorts even though some dropped out. but this wont be due to DLTs, these are drop outs for other (non-trial related reasons).

Yep. saying that the meeting documents and poster presentations are available on the website.

@Woland, great post, thanks for the link to the Keytruda P1 study. Indeed, a great comparator.

Just for clarity, C5 had 7 patients dosed (C1-C4 dosed 22 patients, but 3 were removed and were not included in the cohort results). My guess is that C5 was similar, 1 patient was removed, so there will be 6 in total for that cohort.

@RD, currently ava6k is being dosed (given to a patient) every three weeks. This is pretty standard for chemo, and it allows the body to recover from the hit it takes from the drug. A dosing holiday is when a treatment is delayed, so they may miss one or two cycles and then start again. This is done if the chemo is having too large of an effect on the body. So instead of waiting 3 weeks for the next dose, the patient may wait 6 or 9 weeks instead.

We saw this in the mouse models for ava3996. The tumor was actually responding fairly well to the standard treatment (Velcade), however the mice were losing a lot of weight (which is a proxy for toxicity in mice). Because of the bad side effects, the mice needed to take a 'dosing holiday' (i.e., they skipped a few treatments in order to recover).

Yep. with CT, MRI and/or PET scans.

I'm on it RAH.

"I genuinely thought that fact would not be revealed until part way through P1b. So to say we’re ahead of schedule from a knowledge perspective is an understatement." - I absolutely agree.

The AGM RNS stated that there will be posters on ava6k, ava3996, affimer therapeutics and diagnostics, so I expect an RNS Wed morning saying that copies of the posters are available on the website. Like SD, there is unlikely to be a new announcement, but also like SD, I expect a lot of new 'not material' info to be given. Would be great if they update the SD slides with the results of C5 and maybe even tell us a bit more about the patients that haven't had their cancers progress.

I'll be there, should be an exciting day.

"progression free" is a common oncology term. It means that the tumor is either shrinking /eradicated, or at worst it has not grown or spread. In the worst case (no growth/spread) it is about giving the patients more time alive. As we've learned for STS, this is common, that dox keeps the tumor from growing/spreading while the 6 dose course lasts, but once that limit is reached, the tumor progresses until death. So if it is *only* doing this, Avacta will have extended the life expectancy of the patient by a factor of 3 (if it is 3 times the number of doses, which I think is now the expectation).

If it's better (tumor shrinkage/eradication)...i.e., if it replicates what was seen in mice for colorectal cancer, then all the better (and it's certainly my expectation).

But from a clinical standpoint, both these groups will be bunched together in the 'progression free survival' statistic. And as I posted yesterday (or Friday, it's all a haze now), this statistic is often used as a primary endpoint of a trial and as a direct measure of the clinical benefit of a drug.

Re-reading the last RNS (thanks to RAH on twitter for calling attention to the relevant bits), it seems that (at least) the higher dosage for the P1B trial has not been selected yet. This very well could simply be due to the fact that we know that the higher the dosage of dox, the better the outcome on the tumor (it's just that higher dosages tend to kill the patient too).

AS stated "If even higher doses of AVA6000 are tolerated then this may make a significant difference to the outcomes for patients in the upcoming efficacy study." So higher doses may lead to better patient outcomes. P6 and P7 aren't just for sh*ts and giggles, they may be part of the search for the highest tolerated dose, which could become the standard for some patients.

Then in the next paragraph AS states: "We are keen to progress onto the Phase 1b efficacy study as soon as possible following completion of the dose finding Phase 1a study." Nothing too new here, except he is explicitly calling attention to the 'dose finding' aspect of P1a.

My take away from this, is that the rest of P1a isn't just a formality, the search for the second (higher) dose for P1b continues.