Member Info for jive_turkey

In general, I agree BITL. Point might be a special case though, as they are licensing directly from Avacta, so I could imagine that they would be kept in the know, at least broadly. On the other hand, that $9.5 million payment for the first radiopharmaceutical is pretty small...given the potential market. This was small because it was before it was in humans, ie., before the clinical trial began. So it may not be enough to buy access, i.e., the motivation may not be there for Avacta to share.

@icecool, one of the important things that must be demonstrated for a new drug is that the results (benefits) are dose dependent. In order to prove the effectiveness of a drug, one hurdle for most studies is to show that more of the drug results in a better response (at least until a MTD is identified). That said, the MTD for mice was ~4 times standard dox (thanks for MrA who corrected my ~6 times a couple weeks ago), so there should be plenty of room to run in the ava6k trial. And if you can provide a bigger bang per dose, why wouldn't you do it? That's what P1a is all about, testing the effect (positive and negative) on humans within some pre-defined limits.

Why is it in the trial criteria? Because you don't want a patient whose heart is about to give out due to previous dox exposure in your trial.

@BITL: I agree. I am certain that the trial is extremely well planned. The question, for those of us not involved in the planning or directly in the know, is inferring the meaning of "reaching maximum lifetime cumulative exposure to doxorubicin" in the trial criteria. Does this mean the equivalent of dox injected or, as you nicely put it, or is it measured in the plasma. If it is the later, then they can blow past the 450mg limit. If it is the former, then icecool's (and I believe this is also MrA's viewpoint) point is valid.

Possibly. Alternatively, ava6k may not be counted in the cumulative dox lifetime limit, given that it is designed to be targeted, i.e., to have a drastically lower systemic contribution. AS and FMcL both have stated that the cumulative limit for ava6k could be drastically different than standard dox. It would be odd to state this if they weren't going above the recommended cumulative dox limit.

My hope is that the continue dosing past the standard dox cumulative limit, which will hopefully result in an improved response in the tumour. AS has also stated that it is not necessarily a larger dose that is the goal, but a longer treatment regimen.

And can someone please explain why we should care if "BEGO is on the bid"?

"The FDA will complete a review of the orphan drug designation request within 90 days of its receipt."

from https://www.nuventra.com/resources/blog/orphan-drug-products/ but this is written in multiple places.

As the application is under review (it hasn't been approved or denied) we must be within that 90 day window.

@RD and BITL, it's true that a company can apply based on pre-clinical data. However, Orphan Drug approval is a fairly big deal, and you'd want to put your best foot forward, as approval is far from assured. From the FDA website, it seems that Avacta must have submitted this within the last 90 days, i.e., since the beginning of June. At that time, they would have had 9+ months of data from the clinical trial. It would be ludicrous to not include this, as this would be the first thing the FDA would ask for, i.e., any data that gives an indication of the drug's potential effectiveness. And if it was only the pre-clinical mouse models, why apply 9+ months into the trial?

In any case, this application was made 9+ months into the trial. It would be cynical in the extreme (and a waste of time and money) for a company to apply for this if they knew that the drug wasn't up to scratch.

Indeed very strange. When other companies that I am invested in received Orphan Drug status for one of their drugs, it was treated as a very big deal (and these are big companies), so I am surprised by the lack of fanfare.

It's clear now why soft tissue sarcoma was chosen for P1b. This was on the list of diseases that would qualify for Orphan Drug status.

Well, this brings us back to the old gem of a question, whether the study is limited by the maximum cumulative exposure to dox. To summarise the previous debate, in the clinicaltrials website, it states that the patient treatment will stop when "reaching maximum lifetime cumulative exposure to doxorubicin", which is what MrAs argument is based on. The contrary point of view, is that AS and FMcL have stated that 1) due to the targeted approach of ava6k, it is not equivalent to straight dox (i.e., so it may not count in just injecting it, but perhaps they are measuring it in the blood/urine and estimating from there) and 2) one of the goals of Precision is that it should allow for more cycles to be completed. The second point would be a strange thing to say and emphasise if the trial was limited to the standard cycles of dox.

Finally, all the above calculations (if the trial is indeed limited by the cumulative lifetime injection of dox) would only be upper limits, as many/most patients would have already likely have had a significant amount of dox during their previous treatments (the eligibility criteria states that they cannot have had more than 350 mg/m^2 previously). This would already be ~75% of the maximum cumulative total allowed, meaning that for most of the cohorts, the patients would only be allowed 1 or 2 doses...which to me at least, doesn't make much sense.

As for the duration of each cohort, indeed it was an unexpected surprise that they could move onto C4 so quickly. I haven't checked the validity of the claim, but Myles has posted that the 3+3 design can change after C2, with patients 2 and 3 of the cohort being dosed at the same time (whereas in C1 and C2 each patient had to wait until the previous patient went through 3 cycles). This would also significantly accelerate the process. And clearly, in this cohort (C3), no patients were lost.

I agree that the market for mass sales is basically gone. However, there is still a non-insignificant market for hospitals, care homes, and vulnerable people, both in the UK and abroad, that is still worth shooting for. Avacta won't win on price, but they should win on confidence (i.e., when you have to know the answer). It's not the ship of gold that we were hoping for, but should be a nice revenue stream into the future. Relative to the potential of Precision and TMAC though, it is pennies.

Given the comments on a possible lack of MTD, and the fact that the mouse models used 6x the dox equivalent, there appears to be ample room to keep increasing the dose in the ava6k trial. And I agree with your last point MrR, can they afford to keep upping the dose? Each cohorot takes time (>3 months), so is the expected improvement of an increased dose enough to justify delaying moving on to P1b. I think that if the results show that the amount of dox in the TME is much higher than standard dox (from the biopsies), and with limited/no side effects, this is enough to move on to the next phase. Future trials can be run to see if upping the dose is a good idea.

As for the higher dose, listening to the AGM comments by AS, I think it was just giving a conservative estimate of the next dose level (as this is controlled by the safety committee and hadn't been set yet). Can you imagine the panic amongst some here if AS said 160 mg/kg and they dosed at 150 instead? Oh the horror...

Indeed, that's great, shows enthusiasm (hopefully based on what they have seen so far). The worry is that both are listed in the 'discovery' phase, i.e., not pre-clinical. So it could be quite some time before they are able to enter the clinic.

It all depends how much of the pre-clinical package they have put together to date. If they have been working in the background, it is possible that they can apply to enter the clinic as soon as ava6k data lands. If that is the case, they could be dosing patients within ~6 months. However, if they are waiting to carry out the (expensive) pre-clinical studies until data release, then indeed it will be at least 1-2 years.

Yes, but they both use the Precision technology. Point use precision (which they call CanSEEK) to bring radioligands to the TME. ava6k uses precision to bring Velcade (or something similar) to the TME. Point liscensed the techology first from Avacta, but it is not clear how much development they have done, i.e., how quickly they can get into the clinic. Whoever liscenses ava3996 can enter the clinic within a year or so, as much of the IND enabling studies have already been completed.

@gmcc, no not more advanced than avacta, the question is Point CanSeek vs. the potential liscensee of ava3996. Who would be faster into clinic? While Point liscensed the technology first, it's not clear how much they have done regarding IND enabling studies. Maybe they have carried them out in the background? Maybe not. But we know that ava3996 has now undergone ~8 months if such studies, with 4-6 months remaining (based on Neil Bell's comments).

Indeed, the fact that Point are still pushing CanSeek, given that they almost certainly have access to the data from the ava6k trial, is a huge positive hint. And Point has said, they are waiting for the ava6k results to push ahead with CanSeek.

I'm not sure how much faster they will be able to move than any liscensee of ava3996 though. It's not clear if the first CanSeek treatment has gone through pre-clinical IND enabling studies yet, whereas ava3996 is already more than half way through.

We knew that rodents had higher FAPa levels, but at least I didn't know that it was a factor of 15! (note that the 'higher levels' quoted by Marty McFly was for baboons)

This directly feeds in to 'multiplicative factor' that has been previously discussed, i.e., how much more dox gets to the tumor than standard tissue. In mice it was 18 to 1 (tumour to heart ratio). With 15x less FAPa activity in humans than mice this has the potential to go to astronomical levls, i.e., if everything is linear (which I am sure it isn't, so this is just an example) this could in principle get to 18 * 15 = 270, so 270 to 1 (tumor to heart ratio).

Of course there are two ways for dox to get into the system with AVA6k, either through encountering 'systemtic' FAPa, or through leakage from the TME. I'm not an expert, but based on 1) the very rapid uptake of dox by tissue discussed by Ophidian (suggesting very low leakage levels) and 2) the fact that William Bachovchin's group is looking at the systemic variations of FAPa activitiy between species, leads me to believe that the major pathway of unwanted dox is through cleavage of ava6k from systemic FAPa. This suggests that this multiplicative factor could indeed be much higher for humans than for mice.

Can't wait for those biopsy results!

@Hurst10, seriously, please explain why you think that this is so interesting that you post it nearly every day.

@Hurst, could you please take 5 minutes and explain why you think BEGO (which I assume is one of the MMs of Avacta) is important (as opposed to the others), and hence why it should be brought to the attention of this BB on a regular basis?

I'm not being rude, or taking the p:ss. An explanation would be very appreciated.

Yeah, not to be trusted at all.
https://www.mcgill.ca/oss/article/covid-19-critical-thinking-health/dont-fall-vaers-scare-tactic

VAERS is a real system (although it is a 'voluntary reporting system', i.e., not based on the conclusions of medical professions), and can be very helpful. But it has also been seized by anti-vaxxers to misuse (misrepresent) the data/reality.

"Along with statements from political figures and far-right activists, we found a few websites which repackage data from the VAERS official website and misrepresent them to mislead people. One such website we identified was OpenVAERS. "
https://www.logically.ai/articles/double-check-how-does-openvaers-misrepresent-data

MrA, MTD is quite well defined, see here:
https://onlinelibrary.wiley.com/doi/abs/10.1002/9781118445112.stat07089

It is a statistical measure, where >33% of the patients display dose limiting toxicities. Hence, it takes into account that there will be deviations within the population. These are deviations beyond the obvious, i.e.., as Richob points out, that there are eligibility requirements to take part in the study. You're argument would apply to all chemo/HIV drugs, and yet MTD is still used in all such studies.

Once a drug is actually approved and in use, including chemo, the supervising docotrs will always look at the full health profile of the patient and adjust dosing accordingly. Hence, why you don't treat yourself with chemo. The more info available, the better.