Member Info for jive_turkey

Sorry for spamming the board, but one final thought. As for cardiotoxicity, Avacta have stated a couple times now that they are not seeing 'any cardiotoxicity'. This was not a hope (i.e., 'our goal is side-effect free chemotherapy' - which isn't what precision is offering, it is offering dramatically reduced side effects), but rather seems to be a statement of fact. Perhaps, the dox level of the system need to get above some threshold before cardiotoxicity kicks in? If that's the case, a low dose of ava6k could be used indefinitely. However, as you state, BV, tumour resistance might become a real problem then.

@BV, that's the big question. Definitely beyond my knowledge, but after meeting FMcL and AS at the AGM I have little doubt that they have the experience and expertise to plot the best course of action.

The source, I don't know. But have a look on twitter. They are coming from people who have demonstrated deep knowledge previously. Of course, take that as you will. But I, for one, find myself cautiously optimistic. Definitely nothing that I'd put money behind, but enough to get me up at 7am each morning while on holiday.

It's an interesting point Bella. One thing that is often lost on the BB is that treatment with dox, even for STS, is typically not expected to get rid of the cancer. It can stop the cancer from progressing, at least for some time, and if it shrinks a bit then sometimes other treatments (radiotherapy, surgery, other chemos) can be used to add additional help. But dox on it's own, even as a first line treatment (i.e., in non-terminal cases) only has a ~4% chance of 'complete response' (i.e., the cancer is gone). Even a 'partial response' (where the cancer decreases in volume above some threshold) is only at the ~30-40% level in the highest dose cohorts (75 mg/m2). Then another ~20% or so will have 'stable disease', meaning that the cancer doesn't grow/spread while the chemo is ongoing. So the overall response rate (total + partial + stable) is typically only 60% or less.

The idea behind giving dox is to extend life, not as a cure (typically, although there is always hope). Presumably this is why Avacta stated that they were aiming for a relatively low dose (but still well above the standard 75mg/m2) for many more cycles that traditionally used for dox, as this could double or even triple the expected survival time. Invaluable for many patients.

But now we are hearing rumours of 'complete response' in some C5 patients. This might be a game changer. If this is a wide spread phenomenon (i.e., many C5 and hopefully C6 patients show this) this is a whole new regime. This indeed would be effectively a cure for some. What percentage of patients see a complete response would be a key measurable, and one that is achievable (as a first indication) in P1b.

This is effectively what they saw in mice (90-100% survival rates at the highest dosages...and remember that photo of the liver!), so it wouldn't be too surprising if they found it in humans too. Although, for the world of oncology this would be an absolute shocker.

For clarity, I don't think the re-rate will happen with the data are officially published. Rather, it will come when the data are presented either at a large, international, high profile oncology conference, or announced through RNS in tandem with a media push. But once the mouse results are confirmed...woosh!

Spot on RD (although nothing left in my pot, I'm afraid)!

@Bella

1b should be with first line patients, i.e., those typically dosed with dox (not terminal).

Interestingly, 1a patients were typically deemed terminal, i.e., were not expected to show benefits of further chemotherapy.

AS confirmed at the AGM that they continue to take biopsies, but (at the time of the AGM) the C5 sample hadnt been fully analysed yet.

And we can also compare against Keytruda (annual sales of $21B in 2022). When given for breast cancer as a monotherapy, the progression free survival was just 2.1 months. https://pubmed.ncbi.nlm.nih.gov/30475947/ This is actually worse than straight dox. This does gets significantly better when combined with other chemotherapies, but on its own, Keytruda is only a marginal improvement.

Which brings up an interesting point, the difference between a drug failing a clinical trial or becoming a multi-billion dollar blockbuster isn't nearly as clear cut as we normally like to think. Improvements on patient outcomes tend to be quite small and often near the noise limit in early phase studies. I think that this can explain a large fraction of the failures of oncology drugs in Phase 2 or Phase 3 trials, after seemingly strong results in earlier phases. This likely even holds in pre-clinical trials, i.e., the benefit of a new drug over existing treatments is marginal, but above the statistical significance thresholds.

When asked about why Avacta are confident in ava6k, AS stated that the pre-clinical data were "black and white", meaning that they weren't seeing some marginal improvement that was near the noise limit of the data. The data were clear and compelling. From what we've seen of the clinical data so far (biopsies, side effect rates, etc), the data in humans is shaping up to be the same, i.e., a clear cut benefit over existing treatments.

IMO, there is no way that a company would modify P1B like Avacta have, to make it a defacto P2 trial (i.e., direct comparison against standard of care, changing primary end point to progression free survival rates - PFS) without having high confidence in total success.

The primary end point is extremely important in these trials. If ava6k would fail to beat straight dox in PFS, even if it beat it on safety, the trial would be said to have failed. And a failed clinical trial for an early stage biotech would be a death blow. There was no need for them to change this (PFS as a primary end point) from P2 to P1b. Most trials keep safety and tolerability as the P1a and P1b primary end points. Hence, to do so, gives a strong hint as to what Avacta are seeing in humans so far.

My guess is that they are simply seeing the replication of the results found in mice. Increased efficacy, massive increase in progression free survival and overall survival, and an excellent safety and tolerability profile.

While Avacta are going after Soft Tissue Sarcoma for P1b and likely P2 (and for good reason!) doxorubicin is used to treat a wide range of tumour types that are also rich in FAPa, for example breast cancer.

In fact, until relatively recently, dox was used as a first line treatment for breast cancer. When dox is used by itself (at 75mg/m2 for 6 or 7 treatments) for breast cancer the overall response rate ORR was just 41%. As we know, if one can give higher doses (i.e., by removing the worst side effects) the ORR is expect to increase significantly. The progression free survival (PFS) for straight dox in breast cancer is just 7.5 months. This is just 2.6 months after the 7 cycle treatment ends.

https://ascopubs.org/doi/abs/10.1200/jco.2000.18.4.724

Assuming that with ava6k the patients could handle 2 or 3 times the number of treatments (as stated for ava6k), the PFS time would be expected to increase by another 10-14 months, even if there were no further benefits to ava6k. And we know that there is good reason to believe that the efficacy is much greater, i.e., if the mouse models are taken as an example...and rumour has it that Avacta are seeing that in humans too).

As a comparison, the new big drug in breast cancer treatment is Trodelvy (owned by Gilead who bought it and the rest of Immunomedics for $21B in 2020) *only* results in an increase of progression free survival of 1.5 months, and an overall survival rate increase of just 3.2 months. https://www.gilead.com/news-and-press/press-room/press-releases/2023/6/trodelvy-continues-to-show-durable-overall-survival-advantage-in-pretreated-hrher2-metastatic-breast-cancer

Conclusion: just by allowing the dosing to continue (assuming a 3 week cycle, like of standard dox) for 12 or 18 doses, would blow the Trodelvy (which made up the lions share of the £21B Immunomedics purchase) results out of the water. Add in increased efficacy, and ava6k looks to be a game changer, making Trodelvy and Keytruda look like baby steps.

By all accounts, the P1a ava6k trial is going very well. Safety has been demonstrated and the mechanism of action has been proven (i.e., ava6k is being cleaved and dox is being found in the tumour). For a normal drug trial (i.e., a novel drug), the next step is to demonstrate efficacy, and in principle that is what will happen in P1b for ava6k.

But, as we all know, ava6k is not a normal drug. It is, fundamentally, a delivery mechanism to get dox preferentially into the tumour while largely sparing healthy tissue. We also know that the larger the amount of dox (i.e., the higher the concentration) in the tumour, the more effective the drug is. More dox = more destruction of the tumour.

So, in actual practice, we are only missing one piece of data. A biopsy (or better yet, a few biopsies) of a tumour of a patient treated with the standard dose of naked dox. If the concentration of dox in this/these patients is below that seen in the ava6k case (at any dose level...but we know that the amount of dox in the tumour is a direct function of the amount of ava6k given, i.e., dose dependence has been demonstrated), then ava6k will be more efficacious than standard dox.

We also know that Avacta and co have all the tools set up to process such a biopsy. This is planned for P1b and could come any time after P1b begins.

Just to point out that the article used to start this thread is absurd, likely autogenerated. The current chemotherapy market is well over $50B per year. Keytruda, a single drug, brought it over $18B last year.

Spillage from the tumour is not the limiting factor. It is the systemic FAPa around the body, that is also cleaving ava6k into dox. They are measuring this, and as the slides from SD show, the higher the ava6k level, the higher the amount of dox in the blood (which is expected and is one more proof of the mechanism of action). So yes, there will be an MTD (at some point the dox in the blood will be the same amount as just giving standard dox - although with much more in the tumour). This will be in either C6 or C7, or it could conceivably be even higher and they may or may not decide to keep dosing at higher levels.

@CJ, the first US patients were included in C5. The US/UK arms do not act independently, they both contribute at a given time to the same cohort. So no, we do not expect an RNS about completion of C6 for another ~2 months or so (possibly longer).

For what it's worth, here is my (probably a tad optimistic) guess at a timeline:

ava6k:

-P1b initial results May/June 2024, P1b completion end of 2024. Breakthrough status granted, along with limited approval to market.

-P2 starts end of 2024 completes by the end of 2025 - more full approval

-2024/2025 - start of a number of P2 trials for a wide variety of cancer types (likely co-funded by partners)

ava3996

-P1a trial begins early/mid 2024 - last ~12 months. This will be much shorter than for ava6k due to the experience of avacta now and also likely many of the same sites as for ava6k.

-P1b - 12 months after that (so ending say mid 2026) following the same structure as P1a/P1b for ava6k

-P2 - 12 months after that (so mid 2027) followed by limited approval again following breakthrough status.

-P3 - begins (as well as likely a bunch of P2 trials going for different cancer types)

Thanks, that's an excellent read. This really drives home that what Avacta plan in Phase 1b, is what is typically done in a Phase 2 trial. Typically P1b doesn't attempt to quantify efficacy, and they surely don't typically do a head-to-head comparison with the standard of care (this is generally done in Phase 3!). So Avacta are clearly accelerating the time line to approval/market.

Thanks both. @Baffyman, I would be very surprised if they dosed new patients at previous dosing levels, as that is just not how trials are run. But there may be some confusion (i.e., it isn't clear) due to the fact that there is a difference between number of patients dosed and number of patients in each cohort (i.e., completed patients).

At the risk of moving on from the fascinating discussion of Wynbore's opinions and investment advice, I have a question that some on here may be able to answer.

At the AGM, there was a mention of the number of STS patients in the study so far (perhaps by Andrew Saunders in the afternoon?). Does anyone know what that number is (and can provide a reference)? We know that there was only 1 in C1-C4 (in cohort 3 - although it is possible that one or more of the three drop outs could have been an STS patient as well), so we can work out how many were in C5.

Why is this interesting? Well, it is a measure (in a vague sense) of how much the US sites (MSK in particular) are contributing to the patients in P1a. But more importantly, as RAH stated on twitter today; "If dosing your P1b target population in P1a and then change your primary P1b measures to include efficacy you already have your answer…" . I agree with that.

@O&W - low white blood cell counts is the main reason why standard dox treatments are limited to every 3 weeks...i.e., they have to give the body time to recover to a minimum level before the next dose. The fact that Avacta are openly talking about much shorter dosing periods (1-2 weeks), combined with the link that PL75 just shared, shows that ava6k is not damaging the white blood cells in a way like standard dox. FMcL said that for standard dox, 50% of the patients would have been showing massive white blood cell lose from the first dose.

@pharma, still waiting for the list (taking time before posting wouldn't have led to me guessing which of the dozens of possible drugs you were referring to). For J&J, if you meant Rybrevant, that is a drug targeting a specific genetic mutation, so not generally applicable at all.

But, it seems clear now that you are not actually trying to get information, rather just create FUD and pointless discussion. Sorry that I engaged. Binned.