Member Info for jive_turkey

@Bella - at the AGM, when asked about future Dx affimer products (in particular, the long list of potential products that we were given in multiple presentations back in the lft days), he stressed that it took about 3 years to develop a product and get it approved. One such product (a vitamin based one) is in development, with another 1-1.5 years or so before it is approved (assuming all goes to plan). Hence, he openly stated that investors should not be expecting a rush of affimer based Dx products in the coming months/years. To me, this was the only negative thing of the whole AGM, which overall was fantastic.

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.

Yeah, I hadn’t put this together, but it seems reasonable to me. It would make maximum use of cohorts 8-10.

Thanks, makes sense to me.👍

@BV - I didn't get that they were going to continue to higher dosing levels in the new P1B. I thought that it was going to be just a head to head of 2 vs. 3 week dosing. Hopefully i'm wrong...would love to see higher dosing levels.

The plan is to submit an IND application early in 2024 to enter the clinic mid-2024.

In the recent Vox interview, AS stated that they have seen an "uptick in commercial interest, driven by the clinical data". This can only mean one of two things:

1) He is referring to the data presented before the most recent RNS (end of C6), meaning SD presentation and the C5 completion RNS.

2) BP is seeing the data as it comes in, and their interests have been rising over the past few months.

If (1) is the answer, imagine the surge in commercial interest after efficacy has been confirmed this week.

From previous posts from the "with power" site, my understanding was that these were largely computer generated, i.e., bots found the ava6k trial, saw that it was a P1a and P1b trial, and that Oesophageal cancer was listed, and the bot created this page. Just like we had previous versions that stated Breast cancer. It is pulling it's info largely from the clinical trials.gov site, and also from specific medical centres (MSKCC) once they appear on the clinica ltrials site.

I don't mean to suggest that this is predatory or negative or anything. In fact, my belief is that this is a purposefully created programme to try to get clinical trial info to patients. i.e., those with specific tumour types (Oesophageal in this case) whose primary physician is not up to date on the cutting edge treatments (unlike research institutes to MSKCC). This would be why they never advertise P1a (which is typically restricted to terminal or very late stage cases) whereas in P1b the trials tend to be a bit more open.

@Bella, indeed the J&J deal was for a fraction of future profits (50%), not for the IP. And J&J did a bunch of the commercialisation as well.

AS has stated that to license out ava6k "at this time" (which was spring 2022) was not the best strategy. Indeed, the J&J kind of deal isn't a license deal as such, i.e., it is about sharing future profits and getting a large upfront payment plus milestones. This would give them the cash to bring further drugs to the clinic, including TMAC for sure.

For those that haven't read "For Blood and Money" by Nathan Vardi, (highly recommended) here is an example of the kind of deal and payments Avacta could potentially make for ava6k now that safety and efficacy have been demonstrated.

In 2012, Pharmacyclics was a relatively small ($900M) US biotech developing a novel drug for blood cancer (a BTK inhibitor eventually called "ibrutinib"). It had no other significant drugs in development, it was effectively a one drug company (i.e., no pipeline). The drug was in Phase 1b/Phase 2 studies (note that as a novel drug it had to carry out a large Phase 3 study, so effectively it was at a similar stage as ava6k is now) with 88 patients dosed. Some early efficacy data was starting to show, although there were some significant side effects also showing (and a lingering fear that the drug might actually be making the cancer worse).

In 2012, Johnson & Johnson paid $150M upfront in cash (plus a further ~$850M in milestone payments) to obtain 50% of future world-wide profits of ibrutinib. J&J also agreed to cover 60% of the remaining development costs (i.e., getting the drug into and through multiple Phase 3 trials).

Given the wide versatility of ava6k to treat e.g., sarcoma, lung, breast, ovarian, pancreatic, etc cancers, a likely strategy for Avacta will be to partner with multiple companies with similar deals to the above for each indication. i.e., upfront and milestone payments along with a percentage of future sales for STS, another for breast cancer, and a separate deal for ovarian, etc. Avacta have already hinted at such a deal structure at the AGM (slide 11).

Such deals would provide Avacta with a large upfront amount of cash, and still allow significant milestone payments along with a fraction of future sales. Effectively, it would supercharge the platform.

Equally, Avacta could license out the Precision platform for other warheads (MMAE's as suggested by Myles). This type of deal is harder to estimate the value for, as it depends critically on the likelihood of success that other companies believe the platform will work with their drugs. Having ava6k in humans and ava3996 reproducing the results in mice must be a big confidence inducer.

In 2015, after ibrutinib had been approved in some indications, Pharmacyclics was bought out for $21B by Abbvie, effectively saying that the drug was worth $42B because J&J owns half of all sales. Peak sales of ibrutinib reached ~$7B in 2022 and is now losing market share to other drugs.

From what I've read, partnering with a BP for later stage clinical trials is a common strategy for small biotechs. Given the immense value and versatility of ava6k and the Precision pipeline more generally, I can now see a fairly clear path towards completing P2 for multiple indications in the not-so-distant future (i.e., few years) through partnering, while keeping Avacta independent, allowing them to bring further Precision drugs to market themselves

Breast cancer drug market worth $26 billion in 2022 (expected to reach ~$60 billion by 2032).

Ovarian cancer drug market worth $2.3 billion in 2021 (expected to reach $5.1 billion by 2031).

avacta have mentioned a few times now that while the focus will be on sts in the initial phase 2 trial, they were keen to also begin trials using ava6k on other tumour types. these additional trials are a bit more complicated as dox isn't normally used as a first line defense and/or it is used as part of a chemo ****tail. this means they are typically longer and more expensive, as extensive comparison to existing therapies must be done. on the other hand, other tumour types can easily generate 20x the returns as sts (i.e., sts is a relatively rare cancer). to do this, avacta will need a partner. a typical agreement would be an upfront payment to avacta, plus the partner would cover the costs of clinical development, in return for a fraction of the market (e.g., 50% of sales or getting the us market while avacta get europe, etc).

today, the new cmo said: "beyond that we have potential to exploit ava6000 to treat other cancers such as breast and ovarian and a wealth of opportunities to build our pipeline and partnerships."

anyone fancy a guess at which two tumour types they will be targeting next?

@jfellow - yes, the inference is that a significant decrease in tumour size is associated with a longer survival times. While not a perfect correlation, tumour size decrease is strongly correlated with survival time, which is why tumour reduction can be used as a primary or secondary endpoint for cancer studies. If one wanted to prove that a drug definitively extends life, then trials could last many years...so secondary indicators like tumour size (or white blood cell counts in blood cancers) are often used.

No mention of cardiotoxicity in today's RNS, which made me wonder if they were starting to see some effects in C6. The interview just confirmed a complete absence of cardiotox, "even at these dosing levels, nearly 3x the standard amount of dox". Amazing.

While the ~20% rise in the SP is definitely appreciated, it is a joke given the news that we have received today (along with all the news over the past 2 years). Imagine AZ or Novartis issuing a statement that a drug in development is going to essentially skip P1b and move directly into P2 as it has shown significant efficacy and an unbelievable safety profile. Their MCAP would not lift by ~$50M....rather, it would be in the billions.

We all know the limitations of AIM, a large contingent of short-term investors and rainbow chasers. Also, the Financial Times opinion piece by AS strongly suggested a general problem in the UK markets, either not being allowed to invest in early-stage biotechs or being too risk adverse. As AS stated (also see the links by BV), the US doesn't suffer from this problem, it has individuals, funds and companies that look for early stage - high potential - biotechs.

So why aren't they getting into Avacta? I don't know, but I have a pet theory. While Avacta have put out results to the investment community (i.e., science day, the C5 end RNS, today's RNS, etc) none of it has been officially published or presented to the scientific community. I wonder if this could be holding back the big boys. Maybe they require, or strongly prefer, results put out in the scientific literature, where known scientists are putting their reputations behind the results.

With that in mind, I note that their is an AACR meeting in Boston in mid-October. Avacta have 2 abstracts (one for an affimer study and another for ava3996) for posters. However, it is also common for big results to be held back until the week of the conference, i.e., if Avacta have a talk to present the ava6k results it may not be released until the week of the conference.

This may just be optimistic thinking, but this could be an excellent opportunity to present the clinical results of ava6k to the scientific community. We won't know for certain until October. Otherwise, the AACR general meeting in San Diego in April 2024 is the obvious occasion to get the word out.

Sorry BV, but I must disagree. It makes perfect sense to compare the ava6k dosing level to the straight dox 'equivalent'. The straight dox equivalent is the baseline. It is the number where we can compare benefits and side-effects to. We know that a dose of 209mg/m2 of straight dox would be near-lethal. We also know that a lot of straight dox never makes it to a tumour, or even into the body tissue, it is excreted from the system. And once we know the amount of dox in tumour biopsies from straight dox at a given dosing level, we will directly see what the amplification factor is for ava6k (i.e., how much more dox is in the tumour due to the targeting).

@Wiggly - yeah that is a great question. I don't know. A part of me says "how could they not?" But i don't know the protocol or ethics for obtaining biopsies.

Pivotal trials usually have a head-to-head comparison between the drug being tested and the standard of care. It is not a requirement, but it is usually requested by the FDA. However, there is also usually a 'get out' clause, meaning that if a patient is not responding to standard dox in this case, they can be moved over to the ava6k arm.

With that in mind, it is also not required that P2 makes it to the end. If, after a representative patient pool has been dosed in both the ava6k and dox arms, ava6k is performing statistically better than dox (which could be in the safety profile, efficacy, or both) the FDA can stop the trial and ask avacta to apply for approval.

I would also argue that it would be worthwhile to carry out a biopsy of a straight dox (75 mg/m2) patient to directly compare the amount of dox in the tumour between straight dox and ava6k.

@cj62 - in principle they could have reached the lifetime cumulative dose limit before they hit MTD. But once a cohort is dosed, and they don't find an MTD at that dose level, they can't find an MTD for that cohort in the future (i.e., the MTD will come at a higher dose).

@LLP - once a patient is dosed at a given level (say C3 level) they stay at that level for as long as they can continue to tolerate that dose or their cancer progresses (or in principle, until it goes away).

@icecool: you're right, for the Sept. 2022 results, they did not have a presentation or Q&A. However, they did have one for:

Spring 2023

Spring 2022

Fall 2021

Spring 2021

Fall 2020

Spring 2020

etc.

So, have a presentation and Q&A is not linked to new info. I wish it was, but it clearly isn't, unfortunately.