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The way I wrote that wasn't clear.

What he meant (I think) was that, because of the time it was taking to get to the 3rd patient, he had changed plans from announcing the 3rd patient to saying the 1st patient had been dosed, but then couldn't because of the fund raise news blackout.

AS additionally wrote me that the 1st patient had been dosed some time earlier but that information couldn't be announced because of the news blackout due to the fund raise.

Thank you for keeping us informed. Have a sweetie.

I think now that he answered it, as the email and RNS were worded, to say that there will be slippage of Arm 2 completing by the end of Q2, but without acknowledging that slippage.

But maybe it is as you say, but then I can't see four cohorts being completed until ...the end of July and AS has provided no new timeline for that. So yes, the Q2W study probably won't finish until September.

@Rambo, from the response I got: "“In parallel” therefore means not sequentially as with the Q3W."

You would agree that the first cycle of each of the doses 160, 200, 250 and 310 - all approved as safe by the SDMC for the Q3W study - could be given to patients without the need to have authorisation from the SDMC, yes?

If there have been no DLTs after the 2nd cycle, then that is good enough to say that that dose level is OK (and SDMC approval will be a formality) for the two-weekly dosing as it was for the three-weekly dosing.

@Timster's "I understand it's to increase participants numbers and start to test efficacy. But that's what phase 2 is isn't it."

From the 28 Feb RNS: "The dose expansions are expected to be in several orphan indications including soft tissue sarcomas and the selection of these dose expansion indications will be informed by data from the ongoing two-weekly and three-weekly dose escalation studies."

From yesterday's RNS: "The data from the expansion study will be used to inform the optimal choice of a single orphan indication for the Phase 2 efficacy study which will follow on immediately."

Phase 2 cancer trials: https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/what-clinical-trials-are/phases-of-clinical-trials#phase2

To answer a few points together, with my understanding.

All the proposed (and I suppose agreed with the FDA and MHRA) dose levels in Q2W, namely 160, 200, 250 and 310 were approved by the SDMC as safe in the Q3W study. Therefore it is safe to give the first dose of any of these.

What isn't known is whether it is safe to give the second dose after 2 weeks rather than the original 3 weeks.

The dose escalation part of the study is two doses for each cohort followed by a 2 week observation period so a total of 4 weeks plus time for the SDMC to review.

All the cohorts could be started at the same time or staggered - staggering by 2 weeks for example (IF there was a fixed stagger period) would allow assessment of the first cycle of the lower dose after two weeks before starting the first cycle of the higher dose and the timescale for Q2W for that (fixed 2 week stagger) would be 10 weeks plus time for the SDMC to review the 4th cohort.

Dosing can continue after the second cycle and at the clinicians disgression essentially for as long as there is no disease progression. (This also means that any patients from Q3W still being dosed are not experiencing disease progression.)

Disease surveillance for Q2W will be every 8 weeks ( https://avacta.com/wp-content/uploads/2023/12/AVA6000-Data-Release-13-December.pdf , slide 11), so every 4 cycles. That is for assessing efficacy and long-term tolerability; the safety part finished after the first 4 weeks.

Timster yesterday: "@BV rereading, I think the running in parallel comment is a cohort in the US can run in parallel with a cohort in the UK. (Maybe)"

I have had this response from AS to my question: Does this mean that patients can be dosed at the US and UK sites for the same cohort, which is surely a given as there is only one trial? Or does it mean that, since all the planned dose levels have been passed safe by the SDMC for the 3-weekly trial, the cohorts will overlap, maybe with 2-, 3- or 4-week staggered starts, barring any DLTs?

Response:

"Yes, it ought to be a given that patients in the US and UK can be dosed in parallel since it is a single unified study. “In parallel” therefore means not sequentially as with the Q3W. That has the potential to shorten the timescale which I think is an important point since we want to stay on track to get into the efficacy (expansion) cohorts later this year."

So we should be on course to complete as per the timeline, or thereabouts given the uncertainty around recruitment and possible withdrawals from the trial.

"Some tumours can be treated with pills rather than standard chemotherapy, often meaning fewer side effects." - Quality reporting there from the BBC. So everyone will now want to take pills because there are fewer side effects with pills.

Take home from this news is that there is a diagnostic test associated with a particular type of cancer, for which there are best practice treatments. Kind of like if there was a test for high FAP...

"Administration of doxorubicin in a weekly regimen has been shown to be as effective as the 3-weekly regimen. The

recommended dosage is 20mg/m 2 weekly, although, objective responses have been seen at 16mg/m2 . Weekly

administration leads to a reduction in cardiotoxicity."

https://www.ctc.ucl.ac.uk/TrialDocuments/Uploaded/Doxorubicin%20Solution%20for%20Injection%20-%20%20Pfizer%20SPC%20-%2018.03.2010_15072020_0.pdf

😂😂😂

Or...

🤔 Hmm, I smell a conspiracy theory brewing here. Let's dive in! 🕵️️

So, you're saying that Avacta's announcement today was missing the mention of first line treatment, which, let's face it, is a bit like a burger without the patty - kinda crucial, right? You're speculating that maybe they're not even giving AVA6000 as first line treatment because it's harder to find patients in the US willing to fork over the dough 💰 (or, you know, get their insurance to).

And now you're suggesting that this payment/insurance quagmire could've been foreseen by FMcL, but the other bigwigs (CC, WT, and LC) just didn't want to listen? 🙅️ Maybe FMcL was the lone voice of reason and decided to peace out 💼 before things got too messy?

But fear not, the UK is here to save the day with the NHS swooping in to cover the costs and make life easier for Avacta and the patients 🇬🇧🦸

...was any mention of first line treatment - surely a key point to emphasise in the announcement if AVA6000 was being given as first line treatment? Maybe none are receiving AVA6000 as first line treatment? As far as I understand, first line treatment of metastasised cancers (i.e. people who are late stage but without prior treatment) is a highly desired option for inclusion in Arm 1 C7 and Arm 2, but not a requirement.

So why has it taken so long to get three patients screened and dosed in the US? And why - and when - did Avacta decide to extended the trial sites to include the UK?

In the information vacuum, speculation thrives and I suspect they had great difficulty finding patients in the US who could be recruited for first line treatment. And I suspect that difficulty was because, whilst Avacta would pay for the costs associated with the trial, the patients, Medicare, Medicaid or their personal or works healthcare insurance would have to pay the standard costs associated with their treatment (standard clinical appointments, tests, hospital stays, etc.) and the various healthcare insurance schemes may not have wanted to pay, preferring instead to stick with reimbursing the standard of care first line treatments.

CC, WT and LC should have been aware of the ease/difficulty of doing such a trial in the US. Maybe FMcL left because she foresaw the difficulty but was outnumbered? I posed the rhetorical question here (yesterday? certainly this week) about who the Americans are working for, what they are working towards.

Anyway, the payment/insurance question does not arise for patients in the UK as costs are covered by the NHS and, beneficially, the costs to Avacta will be lower as well. Maybe the first line treatment will now be done mainly in the UK given the easier recruitment conditions and much bigger catchment area (London, Manchester, Leeds, Newcastle and Glasgow, so covering most of Britain), with the US primarily picking up patients who will not get first line treatment. We'll see. Perhaps.

@Bella, yes: chemistry degree, postgrad in information science, worked in pharma companies for 30 years doing patent novelty searches, inter alia.

@Bfdinvestor's "Historically, the first patient dosed in every cohort has been communicated via RNS. This time it is the third patient."

Correspondence received on 24 January, and subsequently relayed here by myself and other(s):

"In addition, because of the safety profile we can dose all patients simultaneously which is different from Q3W and shortens the Q2W study considerably. Therefore we’re going to announce progress in a slightly different way from Q3W and I’m waiting for the moment to do that."

It is, of course, unclear whether all three patients in C1 were dosed simultaneously (over a period of a few days) or when the first patient was dosed if dosing took place over a longer period of time.

AS needs to commit to sticking with attending those BA sessions. Enough of the backsliding already.

No, the whole point of the pre|CISION platform is to target highly cytotoxic compounds specifically to the tumour microenivornment of epithelial cell cancers. Those highly cytotoxic compounds can be either existing approved drugs or cytotoxins that failed before approval because they were too unspecifically toxic to healthy tissues.

@Bella's "Ideal for pre|CISIONTM tumour activation to create safer and proprietary pro-drugs. Conservatively assume the pre|CISIONTM prodrug versions of these can achieve similar market sizes delivering 5-10% royalty to Avacta plus development milestones. Potential for a pipeline of pre|CISION pro-drugs, some of which have already been synthesized, with an addressable market of many $bn pa. Including but not limited to: • preCISION Velcade • preCISION Paclitaxel • preCISION Oxaliplatin • preCISION Gemcitabine • preCISION Capecitabine • preCISION PARP inhibitor • preCISION PD-1 Inhibitor • preCISION AKT inhibitor • preCISION Balixafortide"

Some of these have free amino groups to attach the leaving group to, some don't. Two problems with that. If the warhead has a free amino group, then the 'invention' is obvious to anyone 'skilled in the art' and therefore not patentable unless a leaving group that is neither AVA6000's 5140 nor whatever AVA3996's leaving group is called - and that introduces questions about how inert and cleavable the substrate (drug linked to leaving group) would be. Secondly, if the warhead doesn't have a free amino group then, like with AVA3996, an analogue has to be made, tested in animals and put through full clinical trials.

The "some of which have already been synthesized" are no doubt the easy ones - warheads with a free amino group and a standard leaving group, or possibly any old leaving group as there has never been any mention of whether these other prodrugs (the only ones Avacta itself has produced) have shown any efficacy or even been tested in vitro.

They want to take AVA6000 to market approval in the US for whatever the chosen indication will be in Phase 2.

I sincerely hope they don't plan to manufacture and market it globally for that indication. I dearly hope they don't plan to initiate all sorts of Phase 2 and 3 trials for combination therapies for all sorts of cancers. I hope they find development and marketting partners once AVA600 is approved for its first use, but preferably before.