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Agreed Wiggly. Also, if the clinical results are anywhere near the pre-clinical ones, then the biopsy data will be essential for fast track approval.

I'm a fan of the idea of licensing out 3996 based on the 6k results (likely to Takeda) and keeping 6k in house for as long as possible.

I'm still confused regarding timelines though. We heard last month that they expected 3 or 4 cohorts with the expected completion of P1a at the end of Q2 or possibly spilling over a bit into Q3. If each cohort takes 3-4 months though, this doesn't seem possible (we'd be looking at the end of Q4 at best). It reminds me though, that last autumn, AS talked about "multiple dose escalations" by the end of the year (i.e., within the first ~4 months of the trial).

Any chance you, or one of your legions, could find out how many square feet of lab space Avacta have at White City and how this compares to their previous location in Cambridge? Could provide some nice insight into their thoughts on future progress.

Nope, nothing new and nothing about the USA trial. I think we just have an excited Avacta newbie in our midst.

fingers crossed for an update in the next few days (DE and USA sites coming online).

From the AARC poster abstract: "In vitro cytotoxicity assessments involving human tumor cell lines showed that AVA6000 was between 80-fold to 4,000-fold less cytotoxic compared to doxorubicin."

Now that is some improvement!

I spoke to a friend recently, who is an oncology researcher, about cancer trials, and learned a bit which I thought might be of interest to people on this board. As has been discussed previously, Phase 1a cancer trials select patients who are at or near the end of the road in terms of their cancer progression. They've undergone the standard treatments which ultimately weren't effective. The main reason for limiting Phase 1a patients to (near) terminal cases is that cancer treatments tend to cause a lot of damage, both in the tumor and in healthy tissues. In order to test the toxicity of the drug in humans, these brave volunteers make a big sacrifice in the hopes that others will be helped in the future.

Often, efficacy is not a main objective in the Phase 1a trial. This is because many cancer treatments only work on tumors in specific (often early) phases of their growth. This means that in late stage cancer patients, the drugs are often not expected to work (as these tumors are quite advanced). Hence, it is not uncommon for the drug to have little or no positive impact on the patients in Phase 1a, but once the toxicity is understood and limited so that earlier stage patients can be treated with the drug, the positive effects can start to be seen.

Now the interesting thing for us is that doxorubicin is known to be effective at all stages of cancer development. So if AVA6K is being activated/cleaved as expected, we would expect to see a significant effect on the tumors (size, progression, etc). Hence, unlike other Phase 1a cancer trials, it should be very clear whether AVA6K is working, even at this early stage. The readout of the Phase 1a results this summer then is indeed going to be pivotal.

(This conversation came about as I was asking him about oncology studies, and telling him about Avacta, and he mentioned that we shouldn't expect any real news on the efficacy until the end of Phase II. But when I explained about AVA6K as a dox pro-drug he changed his tune significantly.)

I predict that the DE RNS will be on Thursday this week. The last DE RNS was on a Thursday, possibly suggesting that the committee meets on (every other) Wed. It will have been 12 weeks since the last DE RNS.

In the recent interview (minute 4:25) big Al says "What's more, there are no enzymes in humans that cleave the precision substrate." According to our friend mr. google, there are roughly 75,000 different enzymes in the human body. Seems to me then that this info could only come from the clinical trials, i.e., by monitoring AVA6K, dox levels and products they can see if unexpected cleavage is taking place.

Or at the very least, they have tested AVA6K (or other precision derived compound) in human cells in vitro.

Either way, it shows that the specificity barrier that stopped previous attempts to use FAPalpha to activate a drug have been overcome.

Given that AVA6K was shown to be activated in PDX models (i.e., human tumors) in the pre-clinical studies, it is difficult not to conclude that "it works".

Nice find Hurst10, sold for a bit over 2x the current mcap. This is effectively for one drug to treat a rare blood cancer. Now imagine the value of a pipeline of highly effective drugs to treat a plethora of rare and common cancers...the mind boggles.

I think that there is a bunch of data/results from the pre-clinical studies that we haven't seen. So far we've only been given some of the topline results. You can see this as there was info in the abstract (e.g., 80-4000 less toxic and the osteosarcoma results) that we hadn't seen before. So we may see more details of which tumors were targeted, and what the specific results were. Also, i'd like to hear more about which animal models were used. Most of the results so far have focussed on mice, but there have been some references in passing to dogs and primates, which I'd love to see. The more different types of animals (especially primates!) that this was proved in before humans, the higher chance of success in humans.

Why were the pre-clinical data not widely shared before the Phase 1a data? Not sure. But one idea is that you don't want to let competitors (and companies that may think about a take over) know the details, at least not until its (largely) proven in humans. It is this possibility that gets me excited that they are now finally sharing the pre-clincal studies (from up to 3 years ago!).

Actually, I stand corrected. At 23:00 in the presentation the primary and secondary objectives of the Phase 1a are listed. In the secondary objectives, the second point is "to evaluate the initial anti-tumour activity". So in order to progress to Phase 1b, some indication that it works (better than the standard of care - i.e., dox by itself) will be needed. The planning of Phase 1b, and continued dose escalation, strongly suggest that these primary/secondary endpoints are expected to be met.

Great point Wiggly. Yes, it is not a primary/secondary endpoint for P1a (or P1b), which is normal for oncology, but they surely have the data and know what the effect on the tumor is. They know if it is working and to what degree (grantet only in 7 or 8 people, but if the results are "very consistent" then the picture is clear). Hence, expanding the study to include more sites (including the US) and openly saying that more dose escalations are expected, speaks volumes.

MrA, you do understand that they use the same drug in phase I and II trials, right? The drug doesn't just magically start working in Phase II. Even if tumor reduction/life extension isn't one of the primary/secondary goals of the Phase I study, doesn't mean that it won't happen in the patient. So yes, if the drug works, the patients in the Phase Ia study will see a benefit.

Did anything ever come from the CAR-T collaboration?

4 patients in cohort 1 were dosed. The more the merrier!

As I've written before, I believe that AS's statement of "we'll announce when dose escalation occurs" was off the cuff (it was during the question period and wasn't vetted by the investigators) and shouldn't be taken too seriously. On the other hand, I believe that the slides in the presentation, and subsequent RNSs would have been highly vetted, so that is what we should be basing our expected timeframes on. In the RNS in late November (the successful IND application) everything appears to be going to schedule.

If AVA6k is as successful in humans as it is in mice, the 1st cohort (especially the 1st patient) can continue to be dosed well past the standard max of 5 or 6 doses. They would currently be on their 9th dose (assuming 3 weeks between doses, although with no side effects, one could imagine that that window may shrink). The other 2 in the 1st cohort would be on their 5th or 6th. The plan was to finish Phase 1a in Q2, and to do this, the 2nd cohort would need to have started in mid November or December, and the 3rd cohort would have begun in early to mid-Jan.

My estimate then, perhaps optimistic but based on the official presentations and RNSs (although ignoring any delays from covid, but my friends in hospitals have told me that trials - non-cancer trials, and most other non-covid related practices continued throughout Nov and Dec) is that 9 patients have already been dosed, with the number of doses varying between 1 and 9 times.

I don't expect an RNS with "mouse model results replicated in man", rather a more restrained statement about improved patient response and perhaps no unexpected side-effects (i.e., that the cleaved molecule is cleared from the system effectively).

My two cents anyway.

spot on CO!

That's a good question, and I have no idea. I seem to remember AS saying that 'finding volunteers has not been an issue', implying that the open sites can provide enough patients (going for US sites has little to do with finding more patients, rather it is about the approvals process). However, i've been back through the last presentation and can't find it...unless perhaps it was in the question session. Anyone else remember this?

It's really not that complicated. The standard vaccines fade rapdily, with 2 doses, and omicron can evade them with relative ease a few months after receiving them. Boosters help a great deal (although how long the protection will last is still a bit of an unknown). The US has a very low booster rate...hence the difference in hospitalisations between the US and UK.

I'm with you ES. Listening back to the last presentation, it is clear that they expected to have undergone multiple dose escalations by the beginning of 2022 (and from the RNS with FDA IND approval we know that they were on target at the end of November). So initial results could drop anytime, and they have the potential to be huge (i.e., 9-12 patients having gone through multiple doses). Exciting times.

It depends on where they are marketing. As far as we know (at least I haven't seen it posted), the lft isn't being pushed in europe at the moment.