Member Info for jive_turkey

@PL - absolutely ticked that box. This has blockbuster written all over it.

@BV - From the RNS of the completion of C6: "Therefore, in parallel with the completion of cohort 7, the Company intends to begin a short study to explore more frequent dosing (fortnightly) of AVA6000 as a first line treatment in patients with soft tissue sarcoma. "

Despite coming late to the party in realising that the biweekly (versus standard 3-weekly) dosing will be a first line treatment (i.e., given to patients as a first therapy), I am still amazed by this. Here's what I got when I asked ChatGPT it is "common for an oncology trial to be a first line treatment in phase 1?":

No, it is not common for an oncology trial to use a new treatment as a first-line therapy in a Phase 1 clinical trial. Phase 1 trials are typically the first step in testing a new drug or treatment in humans, and their primary purpose is to evaluate the safety, dosage, and potential side effects of the experimental treatment. These trials are often conducted in patients with advanced cancer who have exhausted standard treatment options or have no other viable treatment alternatives.

First-line treatment in oncology trials usually occurs in later phases, such as Phase 2 or Phase 3 trials, after the experimental treatment has shown promising safety and efficacy results in earlier phases. However, there can be exceptions in certain situations, such as when a new experimental therapy is expected to provide a substantial benefit over existing treatments, and there are compelling reasons to use it as a first-line option in a Phase 1 trial.

Thanks PL! great spot gmcc…dont know how I missed this thread…

Haha, looks like i'm last to the party (don't know how i missed this)...but wow, what a result!

Thanks to Icecool for point this out, I had overlooked this. The "6th cohort completion RNS" states that the upcoming shorter dosing frequency (fortnightly) study is to use "AVA6000 as a first line treatment in patients with soft tissue sarcoma".

This is a massive change! We are no longer dealing with the terminally ill, or those that have undergone multiple previous treatments with limited success, we are now talking about (relatively) healthy patients, where ava6k is *expected* to show efficacy. In fact, we will have patients who would normally be given straight dox, but will now be given ava6k.

The FDA would not approve such a step without serious evidence of expected efficacy. While straight dox isn't overly effective in STS, it is the standard of care, and statistically extends life. So you don't pass on this without good reason.

So even this extended P1a (or short P1b?) trial (or whatever you want to call it) is effectively a P2 trial. They are looking for efficacy and offering this as a first line treatment for patients.

For reference, all the Phase 2 Keytruda studies that I've found (although perhaps not an exhaustive search) were done on patients that have undergone previous therapies that were unsuccessful. ava6k is skipping that, jumping the queue into first line patients. amazing!

@MCB55 - a drug can be approved by the FDA at anytime, including during a Phase 1 study. It is just very rare. When accelerated approval is given, that means that there is evidence that the drug is filling an unmet medical need. In order to turn accelerated approval into 'full approval', a company still needs to complete enough clinical studies to file for approval in the normal way. This normally means carrying out a full Phase 2 and 3 studies.

However, phase 3 trials are often not needed in the case of pro-drugs, so if ava6k works as well as it did in the mice trials in humans (and there are strong indications that it is), full approval will be sought after Phase 2.

If the data are looking very good at the beginning of Phase 2 (of which Avacta should have a very good view on already during the bi-weekly dosing study) they can apply for accelerated approval then. Or if the data are so overwhelming, the clinicians can actually stop the Phase 2 trial and recommend the FDA to approve the drug before Phase 2 completes. Again, these are rare cases...but if Avacta are truly sitting on a paradigm shift in chemotherapy (AS's words) then this is definitely within the realm of possibility.

@Moneysponge: From google: "A Pivotal study that is a trial designed & executed to get statistically significant evidence of efficacy and safety as required for approval."

So yes, this means that a Phase 3 will not be required (unless the data from Phase 2 don't support the application...i.e.., if the results are marginal).

Morning Timmy - While I'm sure Lilly looked through all the current and future assets of Point in extreme detail, of which Canseek will feature prominently, Point of a number of promising treatments in development. Marty, on twitter, pointed out yesterday PNT6555, with is FAPa binding (not releasing) and the pre-clinical data look pretty amazing.

Morning CJ. I think a takeover is a possibility anytime, and as we have seen, it can come out of the blue. That said, my feeling is that, given the optionality of the Precision platform (i.e., attaching any number of generic or proprietary warheads), a series of license deals (potentially with multiple companies) would be the preferred option for Avacta and big pharma companies.

But this is just my guess, I do not have any first hand knowledge. I guess that it depends, at least to some degree, what Avacta will charge for access to Precision.

Hi wcotter - Yes, Precision and ADCs are both delivery mechanisms, attempting to bring chemical warheads directly to the tumours, thereby sparing healthy tissue. Think of ADCs being the current state-of-the-art with Precision aiming to replace them.

I posted the below a couple weeks ago:

Antibody-drug conjugates (ADCs) are all the rage in oncology today. There was a good article in the economist today about them (https://www.economist.com/business/2023/09/21/big-pharma-cant-get-enough-of-one-class-of-cancer-drugs). Effectively, ADCs are very similar to Precision. They take a chemo warhead, attach it to a monoclonal antibody which subsequently binds to a particular receptor on a cancer cell (https://www.astrazeneca.com/our-therapy-areas/oncology/antibody-drug-conjugates.html).

The market in 2022 for ADCs was worth ~$7.5B, which is expected to grow to ~£30B by 2028. The problems with ADCs is that they are very complex to make and their selectivity isn't great, i.e., there is still a lot of off-target (healthy tissue) damage.

The beauty of Precision is it is 1) highly specific, 2) easy to make, 3) cheap and stable.

Hence the future of oncology is clearly targeted therapies, bringing treatment directly to the tumour. But I'd wager that ADCs will soon be outclassed.

@Richob - no, the vast majority of Point Bio's pipeline is not related to Canseek/Precision. It is based on their own technology, with different programmes in different stages of clinical development.

Yes, they have licensed the Precision chemistry from Avacta/Bach, which they call "Canseek", but all this is still in the research stage (i.e., before pre-clinical). However, Point are/were very keen on the possibilities of Canseek and have mentioned them as potentially greatly expanding their pipeline in the future.

Shows that such a take over (TO) can really come out of nowhere. Point Bio share price was down ~17% over the past month. No leak at all.

Thanks Sammy, that is certainly one viewpoint. Personally, I am doubtful that the release of P1a data by itself will significantly affect the SP. Do we really think that there are a significant number of AIM investors who are sitting on the sidelines with money ready to poor into Avacta once they see, interpret and understand the results? That is a very optimistic view.

My take, for what it's worth, is AIM is not a "real" market, in the sense of NASDAQ or even LSE. Pensions funds cannot invest in AIM and there are significant constraints on how large funds can invest in AIM (i.e., risk profiles, etc). This means that the money on AIM comes mainly from individuals and AIM seems to have a high density of traders rather than long term investors. We can see the impact of these traders on the Avacta stock price, with rapid rises to ~180p with the results of the SD presentations and a drop of 50% soon there after. What changed? Traders simply got in for the spike and then got out as it became clear that further results were a few months or more away. In a market dominated by investors a few months is nothing, and we wouldn't have seen nearly as big of a pull back. In fact, if NASDAQ equivalent companies are used, we can see that typically announcements like the SD data, which significantly de-risked the investment, would have been met with large and steady gains over the following months.

Maybe when P1a results are released the traders pile back in and we make it back up to 180 or 200p, but they will then pull out causing the price to tumble again. Covid times were another example, the traders piled in to a handful of shares, driving up the price...not based on any long term sales vision but just popularity.

The only ways out of this cycle, in my opinion, are 1) published license deals which will change the base price of the stock (although the fluctuations from this baseline will still happen) or 2) a major investor (ideally, in my mind, a large pharma company) buys say 20% or more of the available stock. This will remove a large number of shares from circulation and provide 'prestige backing', again limiting the role of traders.

Yes. The pharmacokinetics (PK - essentially how, where and when a drugs moves and is processed by the body) of ava6k is very different to that of straight dox. Hence, it is not as simple (especially from a regulatory point of view) as just substituting ava6k and the standard dox level. Drug approval is a very conservative business, and even in the case of breakthrough drugs, due care must be taken.

Spot on MB.

@Robin - I think you may misunderstand how the media works. When it comes to companies and their results, the media rarely do independent stories about them (perhaps if the companies are big enough, i.e., microsoft, pfizer, etc). Avacta present some results, and I'm sure some journalists saw it or heard about it. They would then contact Avacta to ask for an interview or some soundbites. Avacta then say "not at this time".

For results like this, you wait to have a good and personal story. Ideally, a number of patients with very poor prognoses, who then fully recover. You then combine those stories, along with scientific results and release that all at once. And of course, Avacta won't just release them, they will contact media outlets in the preceding days to set up the big reveal.

So every time you read about amazing medical (or technology) results from a small company that you have never heard of, know that it was that company you contacted the media, and not vice versa.

Yes, the stroma (and hence the fibroblasts and FAPalpha) is present during the development/growth and metastasis of a tumour. However, in general, chemo (even ava6k) shouldn't be seen as a "cure". While it would be amazing, it is not a reasonable goal for a chemo treatment to have a complete response in most patients. For example, many tumours become resistant to chemo, i.e. they evolve complex mechanisms of clearing out chemo chemicals. It is for this reason that the early results of efficacy are so impressive, these are typically heavily pre-treated patients, so their tumours likely have already developed defense mechanisms.

However, as stated today by AS (and by EF as the AGM) ava6k can hit the stroma (and the cancer cells directly) and begin to break it down. This is a major barrier in treating cancers, so if we can eliminate/puncture this barrier and then hit the tumour with another treatment (likely immunotherapy rather than another chemo) this could have a major effect on the partial and overall response rates for the combined treatment.

Once approved (or more likely once a major pharma company is brought in as a partner), I expect a flurry of P2 trials, using ava6k with a range of other therapies for a wide range of tumour types.

Avacta are quite conservative, one step at a time. Fair enough I say at the early stages, but I argue that soon the approach should be multi-pronged study, running many P2 at the same time, maximising treatment options as well as market viability.

@icecool - to be fair, the point was that affimer based Dx products were multiple years down the road. Hence, their value relative to Precision (in the short, medium - and likely long term) would be quite small. The value in the Dx business, at the moment, is through Coris and Launch and their existing products/contacts.

AS just stated that the reason why they can essentially skip P1b is because the efficacy signal in P1a is so clear.

What we know so far about efficacy:

1) "Several patients remain on trial in different dose cohorts and continue to receive AVA6000 as their disease has not progressed" - RNS June 21st

2) "significant tumour volume reduction) has been confirmed in a patient with soft tissue sarcoma on the trial, and there are further indications of clinical activity in patients across other indications." RNS Sept 19th

3) "targeted release of doxorubicin in the tumour has been confirmed both by analysis of tumour biopsies and now by clear clinical responses." RNS today

So, we know that patients in C5 and before were seeing their tumours respond (i.e., not grow) while on ava6k. For C4 patients, they were on 200mg/m2 and there were strong indications that the drug was working. C7 is at nearly double this amount.

As for points 2 and 3, a couple things to note. We are only being told about the extreme case, i.e., the case of a very large and significant reduction in tumour size. If you look at the statistics of drug effectiveness, you don't get a zero response and then one very large response. i.e., for each patient that has a 'very large reduction' (say >50%) you will have multiple patients that show something like a 25 or 30% reduction.

This is effectively confirmed in todays RNS, with the plural use of "responses". Clear clinical responses.

They are giving us bits and pieces, and all will be revealed in the P1a data rollout. How many patients had their disease progression stop and for how long? How many reductions in tumour volume, and how much, have they seen. And for each dose escalation the story is going to get stronger and stronger. Clear clinical indications from at least C3 and at higher doses we expect better and better results.