Member Info for jive_turkey

"there’s something that PI’s are missing" - again, that argument would apply to every single biotech company before their first deal. Why haven't BP gotten involved yet? Oh there must be a problem. Easy FUD until a deal is announced.

That is the point in investing in a company like Avacta, it is early stages so PIs have the opportunity to get in before BP get involved. If you are impatient, move on. Biotech takes time...especially when you are operating on a shoestring budget like Avacta (i.e., all UK early stage biotechs). Negotiations go both ways...i.e., Avacta may not want to do a deal until the price is right. Who knows. But argument that "BP isn't interested because there are no deals" is spurious and naive at best.

Some context and corrections TVC:

-First, it is for a single drug. Not a platform. This deal is only to develop and commercialise XTX301.

-Second, how many deals did this company do before this one? none, at least for this drug. i.e., yesterday you would have put them in the same category that you have accused Avacta of.

-Third, you have no idea what kind of discussions Avacta are undergoing. This deal is a very small one, and if Avacta announced something like this for ava6k, it would be a terrible deal. Why? It gives away 100% rights of the drug and ava6k is going after a much larger market.

-Finally, this is a novel drug with an unproven (so far) mechanism of action. Very different to Precision and ava6k.

Good question Timster. As BITL said, we'll certainly get an explainer video as well as a link to the poster. Note of course, that we don't want a 'full report'...those are for experts going through the details of biopsy measurements, etc. What we want is a top level explainer of the data and key results. So following on something I wrote for the presentation last December, here's what I think we can expect from the video presentation:

-Patient demographics and cancer types (effectively an update of slide 81 from the science day presentation), total number of patients in each cohort. Also like in the SD, some indications of levels of previous treatments (hopefully we see that in C7 the patients were near first line).

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

-Side effects profile (update of slides 82 and 83) relative to straight dox. Hopefully a lot of emphasis on this, with more details concerning quality of life, alopecia, etc.

-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).

-More individual case studies (the patient with STS with large tumour reduction along with others, hopefully also saying which other tumour types have responded). With particular focus on C6 and C7 patients.

-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.

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

-I don't think that it is very likely (since these are not first line patients and also from a diverse pool of tumour types), but it would be amazing if we got some estimates of Progression Free Survival (PFS) and/or Overall Response Rate (ORR).

@B2HS2L - ava3996 (the 2nd most advanced Precision drug in development) is indeed a pro-drug form of Velcade (essentially). They have however said that applying Precision to other generic chemotherapies is likely not the best use of the platform. Instead, they aim to apply it to more modern, much more toxic, warheads (like MMAEs).

That doesn't mean that the work on things like a pro-drug form of Paclitaxel was wasted. Far from it. It was about learning about Precision, what works well and what doesn't in terms of the chemistry. The fact that they were able to already develop multiple Precision forms of known chemotherapies demonstrates the relative ease with which they will be able to develop things like Precision MMAEs.

For those not familiar with MMAEs, they are effectively 100-1000x more cytotoxic than standard chemotherapies. They can be used because they are attached to ADCs (antibody drug conjugates) which selectively puts them on tumour cells. If you put MMAEs directly in the body, the person would die quite quickly. MMAE and similar compounds needed to be developed because ADCs were not efficient enough in bringing drugs like doxorubicin to the tumour. They worked, but didn't work well enough to do significant damage to the tumour. So they needed much more toxic warheads.

Precision works very well with traditional chemotherapies and will likely work even better with MMAE and similar compounds. This, along with other significant problems with ADCs, shows the power of Precision.

True, it has not been officially stated that STS (sub-type) will be used in P2. However, given that Avacta had to apply to the FDA for ODD in STS, which is the reason they are in open discussions with the FDA and Dr. Tap is leading the clinical trials, it is all but assured that it will be an STS subtype in P2.

@Nursesteve - no, we will not hear about the efficacy of the bi-weekly study at the end of April. The committee meets by the end of April and they will decide whether or not to move on to the next cohort and dose level. All we will hear is whether this has been granted or not. We may get some hints on efficacy along the way (like we did for the 3-weekly dosing schedule) but we won't hear much until the end of Arm 2...either because they finish or they find an MTD.

Hi all, I believe that the plan will be to select 2 or 3 different subtypes for P1b (although it is no longer called this) and then select the one with the highest efficacy (folded in with expected patient numbers) for P2. The idea behind this is that you want to put your best foot forward in P2. If ava6k knocks it out of the park in P2 for that given subtype, then future trials will be easier.

Note that approval won't be for all STS subtypes. Why? Because this is a diverse group of tumour types, and some do not respond well to dox.

This is why drugs like Keytruda have gone through more than 500 trials. Before a drug can be used to treat a cancer type, it must go through trials to prove it is efficacious for that (sub)type. This is, at least in part, due to the fact that there exists treatment options for virtually all cancer types. So to be approved as a new therapy, you need to demonstrate improvement in efficacy or lower side effects.

Thanks for sharing gmcc!

Exactly Timster.

Hi GoSushi - I don't believe that Keytruda has been approved for all cancer types that show a certain mutation. As of 2016, Merck had carried out 270 trials of Keytruda (and I believe it is now over 500) testing it on all sorts of cancer types.

Also, ava6k won't work (at least not as well) on all FAPa rich cancer types. Due to the mechanism of action (MOA), it will be more efficacious in tumour types where cells are rapidly reproducing. This limits, somewhat, the types of cancers that ava6k can be applied to. However, it is much broader than most new oncology drugs coming to market (which target very specific subtypes of cancers).

The next step up is ava3996, which should be, by and large, tumour agnostic due to its MOA. Effectively, it should kill most cells.

@dogs - no, they said that they can dose all 3 patients at the same time (unlike in the Q3W study). But it was implied that the 1st patient of this cohort was indeed dosed in Jan or Feb. What the delay was is still unclear (to us non-insiders).

@ATBD - ava6k received orphan drug designation for STS. For Phase 2, Avacta will select one sub-type of STS. Which subtype is presently unknown, but they will likely try two or three subtypes in the P1b (although it's not called this at the moment, but for simplicity, I think we can use it).

But indeed, for other cancer types, they will need to partner up. Officially, they said that this will happen after the P2. However, I think that is ludicrous, so I would expect this to be announced after the P1b studies. i.e., what efficacy is officially measured.

Hi GS - good question, indeed it is not a common phenomenon. I have seen one or two approvals after Phase 1 but I can't locate them now.

What I can find is a few cases (e.g., for KRAZATI) which got accelerated approval after a combined Phase I/II trial. These cases often had P1a dose finding parts followed directly by P2 efficacy studies. Which sounds like the boat Avacta are in.

To be clear, I think that the most likely result is accelerated approval during or after P2, but since this is a known drug, with a known mechanism of action (dox), that is looking to replace standard of care treatment with terrible side effects and limited efficacy, I think that there is scope to move more quickly that would normally be expected.

Muck - yes, i think that for future trials (eg ava3996) they will be guided much more by the pre-clinical trial results. For ava6k i think they were more guided by the usual dox amounts.

As previously inferred and now explicitly said, no maximum tolerated dose (MTD) was found in the 3-weekly study. This is phenomenal in itself, and there are important things that we can infer from this. As we know, they will not be increasing the dose beyond that of C7, although with no MTD found, i.e., they could keep upping the dose if they wanted. This means they are leaving some of the potential of the drug out of the equation. There is little doubt that increasing chemotherapy dosing levels leads to more tumour killing. But they are not going higher.

Instead, they are going for a bi-weekly dosing and much lower levels. Therefore, we can infer that this is expected to be more efficacious than continuing on to higher dose levels. This is in line with expectations from previous studies of dox, i.e., more frequent dosing leads to better cancer killing (but also leads to worse side effects, something that ava6k can alleviate).

Now, if there was any real doubt about ava6k not being efficacious enough, Avacta would have continued to higher doses. Why? Because you wouldn't leave any (potential) efficacy off the table if the results were marginal. Drug development is often done with fine margins. So to leave some potential off the table would only be done if the results are already clear and demonstrate superiority over existing treatments.

Avacta are clearly a very conservative company, not rushing through the clinic and not taking chances. So for them to forego higher doses and not make it to an MTD clearly demonstrates that the results so far have proven efficacy to management/clinicians. Yes, they still need to prove it in the clinic (that is science) but their decision speaks volumes about the likelihood of extremely high efficacy.

We've already seen some great results from the P1a study so far, and I expect that the best results have been held back (as implied in the December Q&A). This includes measurements of the lack of cardiotox, case studies of C6 and C7, and progression free survival estimates, in my opinion. If true, the results to be presented at AACR should be phenomenal.

Precision works, side effects are drastically reduced, and excellent efficacy is all but a given.

My take on the new protocol (the dose expansion efficacy) is that this is effectively a quick P1b. They will likely choose 2 or 3 STS subtypes, and dose patients (likely first line treatments) with the optimal dose found in the bi-weekly dosing study. For the subtype that responds best (also taking into account likely patient numbers) they will take that subtype into P2. The goal here is to get approval as fast as possible. So the P1b will provide direct efficacy results (tumour shrinkage and progression free survival will be the two em observables that will be the most important) and allow Avacta to choose the subtype with the highest chance of (quick) success.

While optimistic, it is possible that FDA approval could come after the P1b study (i.e., before P2 begins). To be clear, P2 will still be required, but ava6k could be on the market while P2 is being carried out. It will, however, certainly provide efficacy data that will help in partnership negotiations with BP. And yes, Avacta will need to partner up (if, for nothing else, than to make enough of the drug) before they hit the market.

My take is that 'first line treatment' was one of maybe a dozen things left out that could have been included (maybe due space limitations, saving news for the future, or simply that every RNS can't cover all bases). Other things that I would have wanted to see included comments is the lack of cardiotox, lack of alopecia, quality of life, an update on Mr. 65% reduction, news from C6 and C7, the types of cancers covered in the biweekly study, the colour of Alan's new car and where did our love go.

@sworaf - I can understand the frustration and I do hope that we get some kind of explanation for what has occurred. However, voting against this would be like voting for Brexit just to say f-you to the Tories. Yes, it will send a message, but it would also be an act of tremendous self-harm. The SP would tank and it would sow chaos on the board, which in turn would likely pause any discussions around LDs or JVs until the boat is steadied (likely months away).

@older - probably either at 1 or 2pm based on previous events.

One of the conclusions in the paper is that high FAP expression is generally associated with worse outcomes (i.e., lower progression free survival) during treatment. The higher the FAP expression, the better Precision does, suggesting ava6k will likely (eventually) be used to tackle some of the hardest to treat tumour types.

@CJ - To be clear, the trial (and changes therein) does not represent a disaster in the slightest. In fact, it's the opposite, the trial has been better than we dared hope for. It is true, that the effective re-insertion of P1b (as far as I can read it) and the reasons for it, could be made clearer to us, but that is far from a disaster.

The SP on the other hand ,and how the placing was managed, could be seen as a disaster if one was so inclined.