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And I agree that approval for STS could well encourage major players to chip in with development and marketting agreements for other indications. I think there will be a lot of trials required for those indications where doxorubicin is barely if at all on the radar as a treatment. Looking at clinicaltrials.gov, there are phenomenal numbers of phase II and III trials to get a drug on the market.

Thanks. I was thinking heavy lifting - blood pressure! Which I knew wasn't correct but...

Sorry, I'm being dim. BP?

Travel_light, you're an idiot. Binned.

I disagree. By your reading there is no indication (or limit) of number for 'earlier cohorts' and that would mean several (at least 3) in cohort 5 and all in earlier cohorts. But no, the 'several' clearly referes to the whole lot, 'cohort 5 and earlier cohorts', so at least 3 patients amongst those in cohort 5 and at least two of the first four cohorts.

Not a lot Ipad. There are two steps.

Firstly there is the bulk manufacture of the chemical entity, AVA6000. This will have been produced in small quantities in the lab initially and will have to have been produced to a high level of purity for human trials. Whether that was contracted out to be done by a chemical engineering company in a lab process (small volume production) or a chemical engineering process (large volume production) I couldn't say. Avacta will need a chemical engineering manufacturing process once they start manufacturing in bulk and that will have to be contracted out to a suitable company.

The second step is to formulate the drug as a finished product: 'bottled, labelled, packaged with patient information leaflet, etc. and that will need to be done in a Good Manufacturing Practice accredited facility with QA and QC, so again contracted out.

How long does it take to set all this up? Well there are availability, contracts, processes, etc issues to be agreed and these do take time to set up so I hope they have started already! One thing I hope they've sorted already is the bulk manufacturing of AVA6000 as that is vital and may even be the subject of a patent if the process is different from the lab process, which it likely will be if they can find a cheaper route to making it.

You must have seen that Trump interview on Fox with Bret Baier then.

For anyone who hasn't, you can watch the fruitloop squirm here: https://www.youtube.com/watch?v=vcLpPa0ZYfo&ab_channel=MeidasTouch

At least 3 patients. Terminally ill cancer patients. So what do you reckon would be their chances of not progressing without any treatment?

Ah, I see your point JT. Thanks for explaining.

I'm not sure I understand your (i) argument JT. For C1 there was a theoretical maximum of 54mg/m² of doxorubicin released. As cleavage was not going to be 100% (that's to say, some would be excreted uncleaved), the amount of doxorubicin actually released would be less than the equivalent of 54mg/m². Similarly for the other cohorts for 81mg/m², 108mg/m², 135mg/m² and 168.75mg/m². Probably only from C3 onwards is the dose of doxorubicin from AVA6000 likely to be greater than straight doxorubicin at 75mg/m² but we won't know the actual situation until the PK data are made available.

Yes, that's why I think they could go for several other indications together once regulatory approval for STS has been achieved. If they get tipped the wink and can organise their manufacturing to come online soon after approval then they, and we, will be laughing all the way to the bank.

Another TW talking point shot down in flames...

Will we get someone giving it a second go like we did with the 'massive doxorubicin doses' talking point?

I'd like to comment on this from yesterday's RNS as it lays out the clinical case for AVA6000 over straight doxorubicin:

"The emerging positive safety and pharmacokinetic data from the study support the potential clinical differentiation of AVA6000 over doxorubicin. This includes: (i) higher dosing of AVA6000 compared to standard doxorubicin, (ii) more frequent dosing of AVA6000 compared to doxorubicin - doxorubicin is typically dosed every three weeks in order for patients to recover from the side effects of treatment, (iii) the ability to administer many more cycles of AVA6000 compared to doxorubicin."

(i) This is ambiguous. We started at 80mg/m² which was, to be pedantic, already a higher dose than the standard doxorubicin dose of 75mg/m².😉 However what's meant is that the doxorubicin cleaved from AVA6000 is higher than the standard doxorubicin dose. Whilst this is already known to Avacta, the clinicians and any companies signing NDAs, it will only become public knowledge when the PK data are release - and will be very interesting to see.

(ii) I sincerely hope that weekly dosing of AVA6000 will be possible in Phase 1b. That would be a change to the study protocol that would expand and speed up best regulatory approval so I hope application to vary the Phase 1b protocol has already been made and granted.

(iii) This to me is the most interesting. Could AVA6000, alone, be used to eradicate cancer, even just one cancer? Doxorubicin only works when cells are dividing and AVA6000 could, I believe, be used in appropriate dose, which doesn't necessarily have to be high, at weekly intervals to reduce tumours. But what happens when the tumour gets really small? All things being equal, a small TME will have little FAP so, whilst FAP is concentrated there, the amount may be comparable to the total FAP in the rest of the body and AVA6000 may lose some or all of its targetting specificity to the tumour and side effects start to appear for any useful anti-tumour activity. Could it kill off all the tumour cells without serious side-effects in other parts of the body or would a combination treatment with another anticancer be better for the latter stages of tumour eradication? Step forward AVA3996? Could these two drugs, in combination, be the Holy Grail for complete remission of epithelial cancers?

Isn't the Fred Hutchinson Cancer Center call for patients with advanced breast cancer not just for Phase 1a, for a cancer type that, as you say, has not to our knowledge been represented in the trial so far? It seems to me that the 'advanced' designation is a giveaway for terminally ill and hence Phase 1a (but I've not seen or read the blurb about it so may have misunderstood the call).

I think they will just go for STS. Reasoning is just that everything is in place for STS as you listed (doxorubicin is standard of care, low survival rates, orphan drug designation, possibility of FDA funding, possibility of fast-track/breakthrough approval for that indication) plus also a second indication would double the number of patients required.

Biopsy data from the most common cancers (including breast cancer) would inform further trials. I can foresee the next trial, once STS has been settled and AVA6000 is on the way to market or on the market and earning money and funding further trials, being for those most common cancer types. That would be a big trial, or several smaller but still big trials, of AVA6000 alone and in combination with another chemo against the standard of care for each cancer type. STS is incredibly easy in that respect as everything is already in place: comparison against standard of care... oh look, the standard of care is doxorubicin. When the standard of care is another chemo or combinations of chemos or chemo and radio, then it all gets a lot more complicated as to which how much more efficacious AVA6000 might be.

Erm... anyone who thinks Monkeysponge has a valid point can sell their shares to me. As the company is such a disaster I'll give you a generous £1 per share. Cash. No need for the tax man to get involved.

As Winit says, the "several patients in cohort 5 and earlier cohorts remain on treatment as their disease has not progressed" means at least two of the patients in at least two of C1 to C4 are continuing to receive AVA6000.

These are the timings of the dose escalations taken from the RNSes, so approximate to within a few days.

C3 (160mg/m²) from 29/06/22 to 31/08/22

C4 (200mg/m²) from 01/09/22 to 17/01/23

C5 (250mg/m²) from 05/04/23 to 21/06/23

C6 (310mg/m²) from ?

So no disease progression has been seen in AT LEAST one patient who started receiving AVA6000 at 160mg/m² in July or early August last year.

The 160mg/m² is 1.44 times* the usual 75mg/m² doxorubicin dose.

* As always when quoting the doxorubicin equivalent or the multiples of the doxorubicin dose, the figure is given as complete conversion of AVA6000 prodrug to free doxorubicin. In reality some AVA6000 will not get converted as it will be excreted before it can be cleaved, so these figures should be read as "equal to up to" not just "equal to". The actual amount converted will be in the PK data to be made public at some time.

In summary, blady fuging incredible result given this trial was looking at safety and tolerability and not at treatment!

All very juvenile.

Asbestos, tobacco, nuclear power, fossil fuels, they've all championed their causes with bought scientists and lobbied politicians.

@OAMOT

An example:

Standard doxorubicin, 6 cycles of 75mg/m² every 3 weeks = 450mg/m² over 18 weeks

AVA6000, 6 cycles of, say, 300mg/m² (202.5 doxorubicin equivalent) every 3 weeks = 1,215mg/m² over 18 weeks

AVA6000, 18 cycles of, say, 200mg/m² (135 doxorubicin equivalent) every week = 2,430mg/m² over 18 weeks

Hello Christmas 2023!

If there were acceptable side-effects with AVA6000, I wouldn't see it going to term; it would be stopped when the efficacy was clear and the doxorubicin patients switched to AVA6000.

So, hello Bonfire (of the doxorubicin protocols) Night!

Wishful thinking perhaps in the AVA6000 doses but AVA6000 is going to blow the bl**dy doors off cancer treatment protocols.

I don't understand HCI's tactics. You'd think it would be in their interest to let the SP rise and feed in their shares to match demand rather than dumping 250,000 shares a day or whatever it has been and drive the SP down.

What news are you expecting before the AGM next Wednesday?