Member Info for jive_turkey

@SB - just to play devil's advocate, here is my take. I think that your low estimate comes from the fact that you adopt each percentage as independent. Whereas, I argue that they are heavily correlated. i.e., if all clinical hurdles and approval is obtained, the chances of the rest go to near unity:

- 70% prob all remaining trial hurdles cleared (= Clinicas CoS)

>>> Given the mechanism of action is proven, the team responsible is knowledgeable, and dox is a well understood drug, I would put this at 90%.

- 80% prob all necessary regulatory approvals are obtained

>>>Given that we have ODD status and if the all the above clinical trials hurdles are cleared, I would put this at 95%

- 80% prob at scale production is possible.

>>>Given that we were told that one of the benefits of Precision is the ease of manufacture and their stability (compared to ADCs), I would put this at 95%

- 80% prob at scale production and distribution can be funded & built

>>>AS has already mentioned that production would likely be partnered out to a BP with considerable expertise in drug production and distribution. So I would put this at 95%.

- 80% prob no better alternatives are developed elsewhere

>>>Given that we have ODD status, no competition is allowed for 7 years. So once it is approved, this goes away. Hence, 100%.

- 80% prob that there is broad adoption

>>>As Dr. Tap said, if you have dox without the side effects, that becomes the standard of care. So let's say 95%

- 70% prob AVCT secures financing through all pre-revenue activities

>>>Again, this is linked to the above, if it is clearing all the regulatory hurdles and partners are brought in for production/distribution, I would put this to 95%.

- 80% prob realised pricing will be favourable

>>> The main competitor to Precision are ADCs, which are extremely expensive. Also this is under the control of Avacta, so it would only shoot themselves in the foot if the put up an absurd price. So this should be 100%.

So then we have: 0.9 * 0.95 *0.95 * 0.95 * 1 * 0.95 * 0.95 * 1 = 0.7 or a 70% chance.

@Timster - exactly.

@AVCT - yeah, I would have liked to hear much more about the cardiotox and how the 7 more cycles was derived (i.e., why 7? why not 4 or 10?).

Piecing together some discussion that I had with FMcL at the AGM and the data from yesterday, we know that they are measuring the amount of dox in the blood at many time points, and can estimate the total dox exposure (AUC). They have a model for what the AUC would be from straight dox. So my guess is that they are going to limit the number of cycles of ava6k to the total cumulative amount of dox in the blood that a patient would have received from 6 cycles of straight dox (at 75mg/m2). This would be a conservative estimate and I think in the long run, if no cardiotox is seen, then the limit on the total exposure will be removed (or significantly raised).

@Timster - the main mechanism of cell death for dox is disrupting the DNA during replication. This happens during cell division. The reason why tumours are killed (in general) by dox more than normal cells is that they grow faster, meaning that the cells reproduce more. However, heart cells do not reproduce quickly or often, so this can't be the mechanism of toxicity for the heart.

So I knew that it was a different mechanism, but I didn't know what the mechanism was.

A google search told me this when I searched for doxorubicin and cardiotoxicity: "Anthracycline-induced cardiotoxicity is due in large part to the generation of free radicals from doxorubicin through mitochondrial redox cycling of doxorubicin in the cardiomyocyte [i.e., a heart cell involved in contracting/pumping], which ultimately results in left ventricular dysfunction, and in the most severe cases, congestive heart failure."

@AVCT - C_max is directly linked to the MTD.

Note that for standard dox, the cumulative dose limit is due to cardiotoxicity. They didn't comment on the cardiotox yesterday, which surprised me, but in the Sept. update they said that no (i.e., zero) cardiotox was seen so far. This is not too surprising, given that the mechanism of cardiotox and the killing of tumour cells by dox are actually different. So it is well possible that the lower C_max, means that the levels never reach high enough values to damage the heart.

@SB - yes, you are right. It's never 100% until the money is in the bank account. However, in the development of cancer therapeutics, all of the additional hurdles are relatively small compared to the main one, i.e., getting the science to work. Additionally, given the clinicians onboard (Tap, Banerji, Twelves, etc) and the experience of FMcL and CC in clinical trials, the risk of a poorly designed P2 (or P1a second arm) is low. But indeed, it is non-zero. And it is true that for a novel drug at the P1a stage, I would also give it a

Hahah...nice one @icecool. For me SD wasn't a big hit as they had two eminent oncologists who gave largely incomprehensible talks that had little or no relation to Precision or Avacta. Nor did they comment on Precision or Avacta. So it was a strange decision to have them speak (in my opinion). For example, a speaker on chemotherapy side effects and the current state-of-the-art in treating the side effects would have been infinitely more relevant to the discussion (since most of those side effects are now being minimised).

Indeed, the presentation yesterday was relatively light on the data, but that makes sense to me, given that it was aimed at non-specialist investors. It is also clear that the data will be published in either journal format or in an oral presentation at a conference.

Spot on @icecool. Deals are not discussed with the market before they are finalised. AS confirmed at the AGM that he had been in contact with companies, and again in September with the 'uptick in commercial interest'. I have little doubt that there have been offers to license out Precsion for this or that warhead. But these offers start low when the asset (in this case the Precision platform) is pre-clinical or early stage clinical. Why? Because there is still risk associated with it. Look how cheap Point Bio got Canseek for? Why? Because it was Preclincal at that stage.

The longer we wait, the more data is gotten, the more valuable Precision becomes. And with the results announced yesterday (and I presume that the data behind it is available now to interested parties) we have broken through a big threshold. It works. Take your warhead, pin it on and send it into humans. With all the PK and biopsy data, I'm sure they also now have detailed estimates/models of exactly how much warhead gets into tumours as a function of time.

Yesterday was a major day in the history of Precision...just a pity that the rainbow chasers that dominate AIM don't see that yet.

@Matml74 - yes, this has been noted previously and it is not entirely clear where the differences come from. My understanding, however, is that, no, new patients are not being added to finished cohorts. The most likely explanation is that while the cohorts had finished at SD, certain patient data had not completed QC (quality control) for one reason or another, hence they couldn't be included. Another possibility is that the numbers are a bit fuzzy because some patients need to drop out of the study (they are very ill, end-of-life patients after all). This is not due to ava6k, but due to health reasons related to their cancers. This creates some fuzziness in the numbers.

And unfortunately no, general population patients are not eligible to use av6k at the moment. That requires approval. There is a path through compassionate use, however, which may be worth looking into with an oncologist.

@Icecool - note that the same tumour type exists in multiple boxes, so the general point still stands. Also, keep in mind that while PFS is used for multiple cancer types, each type has their own PFS number (i.e., timescale), so mixing and matching cancer types is not allowed.

It is “potentially” because it depends on the study being successful. It will only be pivotal if all primary endpoints are met.

And for the PFS list, that list simply makes up >90% of all solid tumours. So they are just saying that for solid tumours (with a few exceptions) PFS is a good indicator.

@Strangy - I think that your frustration is understandable. Avacta have an amazing platform and have presented some spectacular results (for those that understand the goal posts for a P1a study, they know that the results have just been smashed out of the park), but we (investors) still have questions and the SP has not reacted reasonably.

However, note that it would be extremely unprofessional for a company in Avacta's position to say anything of substance about ongoing deal negotations. You don't mention them until they are finalised and agreed upon. Additionally, FDA Accelerated Approval or Breakthrough Status are not things that you state that you are going for, because it sets extremely high expectations and is outside the control of the company (i.e., that the FDA would approve such requests).

As for the media coverage, FWIW, my opinion is that the results presented today are amazing, but not enough to really get the media excited. The reason, as stated by CC clearly in the presentation, is that these patients are typically heavily pre-treated, which is known to limit the effect of further treatments. They emphasised that they are going for patients in the bi-weekly dose study with little or no previous treatment, which is where the big signs of efficacy will be found. So that is, in my opinion, where the media coverage will begin in earnest.

I am sure that these "case studies" will feature prominently in the presentation and any media attention that we get. We were also told in October (through the Telegram Group note) that this patient's tumour continues to shrink.

Yes BV. But who makes up Avacta's shareholders? 99%+ UK citizens or residents.

@Timster - great minds think alike.

This is a presentation for shareholders. Despite what the Hurstbot says, the US does not make up a significant fraction of Avacta shareholders.

@alhal - if they RNS a link to the pdf of the presentations at 7am tomorrow, that will more than comply. This is what they did for the AGM this year, if I remember correctly.

We found out that one STS patient had seen a dramatic decrease in the size of their tumour at the end of C6. However, we also know that (at least for C1-C4, and the timings for C5 & C6 suggest the same) that the median number of cycles of patients is 2 within the cohort window. Typically, it takes more than 2 cycles of dox to see a large decrease in tumour volume (although there is significant spread on this). Put this together, and it suggests that the STS patient may have come from C5. Also, note that it was at the end of C5 that we first started hearing rumours that patients were responding.

Ok great. If that's the case we might get some spectacular news tomorrow on C6 patients. They are at a higher dose than C5 and, assuming they stayed on treatment, would have gotten 4+ doses by now. So they would be in the window of seeing dramatic response by now (probably not so much for C7, although given the higher dosage, one never knows).

So that first STS patient may just be the tip of the iceberg when it comes to efficacy.

Roll on tomorrow!

@PL - yes, it would be great to not have the standard Precision intro. On the other hand, if this is the presentation that they are going to use to get the media involved, a big (and repetitive) is needed.

@Rambo - absolutely spot on. The Q&A session is a mere formality and not the focus of the meeting. I, for one, would rather them not waste time on Q&A (most of the questions will already be covered in the presentation and most of the rest will be on topics that the company are obviously not going to address) and rather use that final 10 minutes to hear more from AS, FMcL and CC.

First thing, RNS at 7am with a link to the presentation slides. Possibly with a high level summary of the data in the RNS text.

In the presentation, almost certainly we will hear about:

-An introduction to Precision and ava6k

-Patient demographics and cancer types (effectively an update of slide 81 from the science day presentation), total number of patients in each cohort.

-Detailed PK results, along with interpretation and comparison with dox.

-Side effects profile (update of slides 82 and 83) relative to straight dox.

-Biopsies update (update of slide 84), hopefully a nice plot showing concentration of dox in tumours vs. dose level (i.e., demonstrating dose dependent results).

-Individual case studies (the patient with STS with large tumour reduction along with others, hopefully also saying which other tumour types have responded).

-Perhaps more detail on whether/how many patients are still receiving ava6k and from which cohorts and cancer types.

-A discussion of the (complete?) lack of cardiotoxicity, how this is measured, and what this could mean for the number of cycles (lifetime limit) of ava6k given. This should be directly related to the Progression Free Survival (PFS) timescale, although I doubt that they will estimate this from the data in hand.

****-A summary of the tumour responses on the RECIST scale (partial response, stable disease, tumour progression) and comparison against straight dox.

-An update on the bi-weekly trial (has it begun, if not, when, what is the initial dose level?).

-Perhaps a slide on the planned Phase 2 study structure.

-Likely a general comment about an uptick in commercial interest with no details.

What we are unlikely to hear about:

-Potential commercialisation and license deals as these will not be commented on until they are made (you don't discuss them until they are finalised), which may only be days/weeks away after the P1a data are released.

-Partnerships for P2 for STS or other indications (same as the above, no discussion until deals are final).

-Plans for media coverage, other than 'strategy is in place' (again, you don't comment on something that you have little control over, otherwise it could look like a failure).

It is unlikely, but possible (if the data are good enough) that they could give us a response rate (ORR) for Cohorts 5 - 7 (assuming the majority of the patients are STS) as you generally don't mix cancer types in this kind of estimate. But this is likely wishful thinking.