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And since their valuation has a generic 'chance of success' of ava6k that is only tied to the clinical stage the asset is in (i.e., Phase 1a gets a 10% chance of success) it will likely jump by a factor of 2 or 3 when we enter P1b/P2.
For me the major difference (as Avacta's technology appears to have a much larger longer term potential) is that Profound is a US company (not listed) and when it raised cash in Feb, it raised $130m, not a token sum of $30m. This type of raise (as it had done previously too) has allowed it to take three assets into the clinic in rapid succession. If it was for being perennially running on fumes, Avacta should have brought ava3996 and likely an affimer into clinical trials already.
Raising money in the UK is a suckers game, the markets can't and won't appreciate young biotechs.
For those that say "it's a difficult market to raise money in", I'll respond by saying only in the UK. US biotechs are surging and seemingly not finding it difficult to find funds.
Some will bring up the Dx acquisitions. Obviously, I would be against those as well. But from what I hear, those were a requirement of the raise at the time.
Yes, I'm upset about the 50p placing for pennies and paying back the loan is a kick in the butt. But the real tragedy is that the rest of the pipeline (ava3996, the rest of Precision affimers, and TMAC) is so delayed due to the lack of funds. These have all been pushed 18+ months behind, at least.
That's just a page from Myles McNulty's excellent research note from last year.
@AVCT - That seems very unlikely. Given that AVA7000 and 7500 were developed for Precision (FAP activated). Also, sucrose is not up-regulated in tumours as far as I know.
This could be simply part of the detailed study work on the two drugs. For example, sucrose is used in many staining techniques to study the effects of drugs on cell lines. Just one possibility of many.
But you are right that even through FAP-rich tumors make up more than 80% of solid tumours, and solid tumours make up the vast majority of cancers, it doesn't make a lot of sense to keep making new prodrugs along this line. On the one hand, we know that each chemo, with its own mechanism of action, is better at attacking certain tumours (e.g., dox goes after tumours that are reproducing). So in principle, it could make sense to have multiple Precision drugs. On the other hand, having a tumour agnostic (e.g., ava3996) treatment, which would also likely include very potent warheads, would likely outperform the individual Prodrugs of Precision. Hence, I am sure that Avacta are thinking long and hard about their strategy of licensing Precision and further Precision candidates. No point bringing multiple drugs to market that end up eating each others market share.
Yep. https://aimchaos.com/wp-content/uploads/2023/02/avacta-group-validation-of-precision.pdf
This is from Myles McNulty's research note from 2023.
Interesting, as ava7000 & 7500 are for Precision paclitaxel and oxaliplatin, respectively. From recent communications, applying Precision to classic chemos like these is not the plan for Avacta, instead they are looking at more toxic warheads (e.g., MMAEs).
@TVC - then invest in Xilo if you think that they are ahead or better. If that's what you think, great. I think your evaluation is spurious. From what I can see, Avacta are years ahead and with much greater potential. So that's where I'll put my money.
"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.