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@BV - good point. Looking quickly at the literature, it doesn't seem that drugs are only approved for specific sub-types of soft tissue sarcomas. So it may be a case of selecting the sub-types where the best signal is expected in order to get approval and then use it for other sarcomas.
Because we were told that it is a relatively simple application to the fda, and that they expected to start the bi-weekly dosing concurrently with the completion of c7.
@Robin - I expect Avacta to issue an RNS when the FDA decision comes through.
I believe that the fastest cohort so far completed in 60 days. Based on that, the earliest C7 could be expected to finish would be the week of Nov. 20th. Before that I would expect news on the FDA decision on the bi-weekly dosing.
200 mg/m2 (135 dox equivalent)
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@Timster - correct, there are a surprisingly few number of papers with dox measurements in biopsies in the literature, despite being such a commonly used treatment. There are a few that I've found that take biopsies after ~1 hour, but the dox levels change significantly over time. I've found a couple papers with models of the amount of dox expected to be found in tumour and other tissues as a function of time, but none with real data in it. From the models, ava6k appears to be doing well, but again that is only at a specific time point, and not the integral over time (area under the curve - which is the important measurement).
Anyway, I think that the crucial observations so far is that multiple patients have had their tumour progression halted (i.e., remain on ava6k) and at least one has seen dramatic tumour reduction. Earlier in the trial AS made a big effort to temper our hopes up, i.e., that efficacy would not be seen in P1a due to the patient population (end of life patients after multiple lines of treatment). Yet here we are, P1a with clear signs of efficacy. In Cohorts 5 and 6, 13 patients were dosed, and I assume all/most were STS patients. Add another ~5 in Cohort 7, and we're looking at >15 STS patients dosed (minimum) in these later cohorts (high dose levels). Should see additional patients with 'dramatic reduction' in tumour volume, hopefully with some details released with the P1a readout.
Good questions BV. Unfortunately, I have seen any papers with those comparisons, in fact I don't think I have ever come across a paper (on dogs, mice or humans) where the dox levels in-vivo and in-vitro in terms of IC50 were compared. I'll keep an eye out for that, good point.
@RMFATGB & @Rambo23 - yes, we know that dox is getting in the tumour, proving the mechanism of action. We've also seen estimates of how effective these levels might be (i.e., IC50). However, there is a tiny risk here, as those numbers come from in-vitro experiments, not in-vivo (i.e., in a petri dish instead of in a human). And that's ok, the data just don't exist at the moment to do the comparison in humans. They planned to do the comparison in P1B (before it was changed, i'm not sure if it is still planned) of dox in biopsies when using ava6k and straight dox, so a direct comparison. Ideally, we would simply see that there is X times more dox in the tumour when using ava6k over straight dox. But it may not be as simple as this, as this would only be at a single time point. Due to the very different PK profiles of straight dox and ava6k (half-life and elimination time) a single time point may not teach us much. What we need is the integral of how much dox is in the tumour over time, i.e. the area under the curve (AUC).
This is exactly what they showed in the mice models, it was in the AUC where there was 18x more dox in the tumour than in the heart.
@DTW - I agree entirely. These are only 'risks' in a very inclusive sense, indeed the real question now is on the level of improvement. I just wanted to respond to the rubbish about 'risk' that FUDders keep brining up here and on twitter.
@Ticino - dox only kills cells that are currently reproducing (as it gums up the DNA replication). Tumour cells have a much higher reproductive rate than typical cells which is why it typically has more effect on the tumour rather than on healthy tissue. It's a very powerful drug although it is not 'tumour agnostic'.
Agreed DTW. In my view, there is only 1 risk remaining, because there is only one bit of info that we are missing. We don't know how much dox is in the tumour when using ava6k vs. straight dox (not just at a single point in time, but integrated over time) as well as what is the ratio in the blood.
Now, that said, while we don't have the actual numbers, there are good reasons to think that things are good to great with ava6k. They are 1) the pre-clinical results in animals, 2) the "therapeutically relevant" amount of dox in the biopsies of the tumours, 3) the fact that many patients remain on ava6k, meaning that their tumours have not progressed, 4) at least one STS patient has seen a dramatic decrease in tumour size as well as strong evidence of effectiveness in other patients (last RNS).
So we know it is safe, we know that the mechanism of action is working (cleavage preferentially in the TME), and we know that some patients are seeing beneficial response. Hence, the risk of not enough dox being released in the tumour is very low.
Thanks BV. Yes, there are definitely other options (like the one you suggested) as well. I should have prefaced my post that it was based on the statement (and slide) at the AGM that "The Precision Pipeline is now entering the commercialisation phase". I should have also mentioned that at the AGM, AS (in the presentation) emphasised the likelihood of point 7 in "the near term".
5) a Joint Venture for ava6000 - An example here would be Johnson & Johnson + Pharmacyclics. We'd be looking at a ~$100-200M upfront payment, with an additional ~$1B in milestone paymets. This would be for a 50/50 split on all sales, and with the big pharma company paying most of the further clinical costs. This type of deal would A) give Avacta a bunch of cash to supercharge other assets, B) allow the trials needed (Phase II) to get ava6k approval for many other indications (breast, ovarian, etc) and C) provide a massive endorsement to the Precision technology.
(https://www.pharmatimes.com/news/j_and_j_pays_$150_million_upfront_for_pharmacyclics_cancer_drug_979916)
6) a Joint Venture for ava3996 - Similar to the above, but probably a lower monetary value, simply because it is in earlier development. However, the target of opportunity is much larger than for ava6k (which is very large in itself) as it may be 'tumour type agnostic".
7) license out Precision for other companies to put on their own proprietary warheads (MMAE's, etc). My view would be that these kinds of deals would look 'pre-clinical' with a relatively low upfront payment ($10s of millions), but with large milestone payments (and potentially some royalties).
My preference, for what it's worth (which is not much), would be for 2 and 7 in the near-term, with 5 close up behind. This would allow ava3996 to be kept in house, and at the same time accelerate ava6k to patients in many cancer types.
AS mentioned 'optionality' when asked about funding recently, so what are the options and general expectations? Below are 7 options which I think are possible.
1) Fund raise - this would result in dilution (which AS has stated they will try to avoid). However, if this would be a private sale to say, a large pharma company, it could actually end up being a very good thing. Effectively, this would mean the backing of a large pharma vouching for the pipeline.
2) license out one or more of the Precision pipeline products (e.g., oxaliplatin). Avacta have stated that they have already worked out the basic chemistry of many of them (ie., created lab versions). While these are all pre pre-clinical (i.e., very early stage) I would suggest the pharma companyies could look at them as pre-clinical, as they are 1) standard chemotherapies (so no suprises there) and 2) the mechanism of action of Precision is already proven. So I think the overall risk of these products is low. Recent pre-clinical license deals for ADCs have been for ~$50-60M upfront, with an additional ~$400-500M for mileston payments. Recent example include AstraZeneca (https://www.fiercebiotech.com/biotech/astrazeneca-spying-post-bcma-big-bucks-pays-55m-adc-join-peers-hot-cancer-space)
3) license out ava3996. This is pre-clinical, but like above, I believe the risk is quite low, given the fact that the Precision MOA has been proven, and Avacta can point to clear evidence that Precision works in humans. Also, they now have a ton of data in animal models for ava3996 (mice and dogs) which one can compare against ava6000. The bigger question is on the effectiveness of AVA2727D (the warhead). As this is in the very last stages of the pre-clinical work, I would argue that this could be seen almost as early stage human clinical trials (i.e., the MOA is known, but the effectiveness is uncertain). A recent example is Merck buying 7 ADCs from Kelun-Biotech for $175M upfront, and possibly $9.5 billion in total (https://www.merck.com/news/merck-and-kelun-biotech-announce-exclusive-license-and-collaboration-agreement-for-seven-investigational-antibody-drug-conjugate-candidates-for-the-treatment-of-cancer/). While this was for 7 ADCs it was not expected that all would make it to the clinic.
4) license out ava6000 for a specific tumour type (i.e., breast, ovarian, pancreatic, etc). I couldn't find many examples of this kind of deal, but Avacta have hinted at this in previous presenations (i.e., at the AGM). My guess is that this would effectively be like licensing a drug that was developed for a single cancer type, so would follow those kinds of deals...so maybe in the low $100Ms upfront, with another ~billion in milestones + royalties.
(continued below)
@icecool - thanks, i had missed that (patient numbers). and i agree, once part of a cohort, the patients can continue treatment but wont join another cohort.
Hi Icecool, where did you see that 5 patients have been dosed in C7? From the results presentation, I just saw the standard "3-6 patients" estimate.
FWIW, I think this cohort will take the same amount of time as recent cohorts (60-80 days). Remember, the bi-weekly dosing is also doing dose escalation, so even if they are starting at dosing levels below C7, they may end up dosing higher (after a couple dose increases). I think that the detailed PK data (and potentially biopsies) for this cohort, due to the very high dose, may be very informative regarding how the body deals with ava6k, leaving time, amount of dox in the system, etc. So it is definitely not one to skimp on.
@Bella - you're absolutely right, one should never underestimate the role of side discussions and contacts. However, when presenting new results to the community (be it science or investing) one wants the largest platform as possible, to spread the word far and wide.
@BV - indeed, I am certain that the choice of where/when to present has already been made. Abstracts for talks are typically due a few months before a conference (with an additional deadline of ~4 weeks for new/exciting results).
EMSO is definitely a possibility RAMBO. I wasn't aware of how large the Jeffries Healthcare conference aware, apparently the large in Europe. So that's a possibility as well, good spot.
The JP Morgan and Jeffries conferences are more business/investor orientated (new results can still be presented) and may be better for media attention. EMSO (and others like AACR) are more science focussed (although of course the major pharma companies will be represented). But I would be surprised if the results aren't released as part of a conference...it's the standard way to bring more attention to the results.
Great point, ava6k should strongly increase the effectiveness of immunotherapies, so future combination therapy trials are definitely in the works (although the first P2 trial will be ava6k as a monotherapy).
Just one note, ADCs won't be improved by Precision. Precision is effectively a new (and better) version of ADCs. The goal of both is to bring the warhead straight to the tumour cells and space healthy cells. What we can do, as pointed out my Myles, is to adopt some of the extremely potent warheads that are put on ADCs and put them with Precision.
As I wrote last week, one way to look at the Precision platform is to see it as disrupting the ADC market (which is currently all the craze in oncology)...which is currently about $10B per year and expected to triple by 2030.
@Doggy - I believe that was just about AS giving a more layman's description of the posters.