The latest Investing Matters Podcast episode featuring Jeremy Skillington, CEO of Poolbeg Pharma has just been released. Listen here.
Several ways I can think of to defend against a cheap takeover bid, and I think we’re seeing this play out:
- Attract more “sticky” and/or knowledgeable shareholders
- Educate existing shareholders about the potential value to make them less likely to accept a cheap offer
- Get the sentiment and share price up appreciably before results are released
- Generate interest across the industry such that any low-ball offer on good results is likely to be met with counter-bids
- Keep a strong balance sheet
I feel like we’re seeing a lot play out to support these lines of defence, one way or another:
- The total pause of LFT sales, drop to 40p and subsequent rise from there has done a lot to shake out many fickle holders that might have been in it for a quick LFT buck. It is a bummer that a lot of PIs will have sold early and lost money, but many of those are likely the sort that would take a £2/£3 offer just to get back to about breakeven with a sigh of relief.
- Shareholder education has been ongoing all along to explain how the chemotherapy is the main value driver, and that has finally landed I’d say.
- Experienced industry/oncology advisors brought in to advise on strategy ahead of the big reveal.
- They are talking up licensing out AVA3996 to provide working capital to support going alone on AVA6000, to give balance sheet confidence.
- Avacta being put in the shop window with the AACR presentation, IND filing and trial hospitals brought on in the US. I’m sure a lot has been going on behind closed doors as well, and I’ll bet the new advisors have made a lot of connections for us. The big players are definitely aware and watching.
Even more succinct take, from Ophidian:
https://twitter.com/ophidian18/status/1513816448057155585?s=21&t=01qD9QqSLu8HjAvyeIn26Q
Nice find Poirot. Finger on the pulse as ever!
Another nice thread, thanks RB40.
Some variable interpretations of the rat and dog tables between the different explanatory threads.
I see some focus on maximum concentrations in one thread, when it’s more correctly the AUC that indicates cumulative exposure.
Also some mangled explanation of AUC in another.
In turn I could be wrong about “5140” not being excreted by dogs. That interpretation is based on the 1/2 life and clearance rates being ND (not determined), and comparing the ratios of AUC, T1/2 and Cmax between different components; AUC looks relatively high for 5140 in dogs. But it could mean instead that dogs metabolise and/or excrete it extremely quickly, if it means concentration rapidly reduced to undetectable levels after too few data points to do the half-life calculation. This is a more favourable interpretation for the drug, as you want the by-products to clear from the system without building up or doing any harm. Evidently it clears fine in rats.
We await the definitive guidance of Big Al.
Ah Roy’s done a good job in even clearer terms! Hope AS gives us some more of the details as well as the grand overview. Thanks for sharing.
Then the last two tables… These are completely new, and the main things to understand. Each one shows results from injecting AVA6000 into the animal and measuring the concentration in blood plasma of AVA6000, the 5140 leaving group, and released Doxorubicin, at regular time-steps afterwards.
Cmax is the maximum concentration observed, and Tmax the time at which it is observed (note this is labelled wrongly on table 3).
AUC is the area under the curve (on the plot of concentration vs time) - this is the cumulative systemic exposure. Both columns are similar - one is extrapolated from the last observable point.
Apparent T1/2 is key. This is the half-life in hours of the component. It indicates residence time in the body of the component.
Some observations:
- Cumulative systemic exposure to AVA6000 is about 6x that of Dox in the rat, and 3x in the dog. I think this is good.
- 5140 is not being cleared from the system of the dog. It would be good to know why, and the excretion mechanism in the rat.
- Dox seems to have a much longer half life in the body than AVA6000. Partly this is because Dox is continuing to be released after injection. It would be good to see the Pk for basic Dox, but I’m sure that’s out there.
- I’ll hold my hand up as a non-expert and say I don’t yet know fully what the last two columns mean. Happy to hear from others on this.
There’s more but I’ve got to get to work! Interested to hear others’ thoughts. It looks like some great additional data and I look forward to hearing more on its significance from AS.
Here’s my take on some of the poster’s contents, hopefully of use if it’s baffling anyone:
Left column:
Intro is self-explanatory.
Note that they are calling the post-cleavage preCISION substrate “5140”. When AVA6000 is cleaved in the presence of FAP, this is the non-Dox part, or “leaving group”. One of the key questions in the Pharmaco-Kinetics (PK) data is what happens to this? Part of the poster later looks at whether/how quickly that is excreted in rats/dogs.
Table/graph bottom left show the high specificity of AVA6000 to FAP, compared with similar molecules.
Middle column - in vitro tests (vs cells):
This column basically shows that AVA6000 is orders of magnitude less toxic to typical cells than Doxorubicin, and that it is activated by the presence of FAP. The key part is the table at the bottom. Each row is a different tumour cell line, or type of cell. Note the second row, HEK-mFAP, which is modified with increased FAP on its surface. The columns from left to right show the effects of:
- AVA6000 when inhibiting the cell’s FAP (expect lower cleavage of AVA6000, keeping it inert)
- basic AVA6000 (more sensitive to cell lines with high FAP expression)
- AVA6000 with added free FAP (cleaves all the drug for a Doxorubicin party)
- Doxorubicin on its own for comparison.
The bigger the numbers, the more of the drug mixture has to be added to the cell culture to inhibit growth. Small numbers = high cytotoxicity.
Right column - In vivo experiments:
This is the key bit, especially with the dog/rat models. Some key questions to consider are:
- What is the systemic exposure to Doxorubicin, vs AV6000? Although in its inert form AVA6000 may be 80-4000 times less toxic to cells, once it is cleaved, the Dox is just as toxic as usual. Dox may be present outside the tumour due to escaping the tumour after AVA6000 cleaves there, and/or due to AVA 6000 cleaving in other parts of the body where FAP is present.
- How quickly do the by-products leave the body?
The top table shows a positive effect against the PDX human tumour cells implanted into a mouse. Notably, this tumour had previously been subjected to three chemo treatments without effect.
Then the last two tables…
Sounds interesting. But where is this from, and which drug are you talking about? AVA6000’s not approved yet, so assume it’s something else, but shows the clinical need?
To the original poster’s point about Doxorubicin levels in the tumour.
It seems intuitive (if not a given) that the ratio of Dox in the tumour vs heart would stay similar across a range of doses. They showed that in mice they could mimic the original absolute concentration in the heart with a 6x dose, giving 18x concentration in the tumour. So if you’re right about 3x standard concentration in the tumour, there would correspondingly be a 1/6th of the standard concentration in the heart.
But then note AS’ comments from the presentation. The fact that free circulating (non-tumour) FAP is higher in mice than in humans, means that ratio could be higher than 18:1 in humans. Then you have to balance how effective you want the drug to be, vs the side effects introduced as you elevate the dosage. There is extremely low chance of getting zero side effects as a lot of people seem to think, but “dramatically reduced “ side effects will do very nicely indeed.
That’s a very interesting question RD, and a line of thinking that could ultimately lead to very patient-specific doses. I guess if you dosed more AVA6000 than there were FAP in the tumour to accommodate it, the question becomes - how much of the excess AVA6000 is cleaved in healthy parts of the body vs excreted in its whole form? Which I think comes down to rate of uptake vs rate of excretion.
Perhaps they could end up with some sort of a treatment plan where they gradually ramp down the dose as they approach this theoretical saturation point and monitor the patient’s blood to estimate when it has been reached, eg if whole AVA6000 residence time increases to some baseline level that would be expected for a healthy person with no tumour.
But we’re getting ahead of ourselves maybe… It does raise the relevant question for this trial of whether the maximum dose might be less universal, and more tumour-size dependent. Perhaps it will ultimately be based on where there is no further benefit, rather than what the patient can tolerate. But this trial is aimed at assessing maximum tolerable dose in late stage cancer patients, where you would assume that there is unfortunately plenty of FAP in their tumour(s) to accommodate all the AVA6000.
Congrats on landing the big job! Hope you and the lads are tucking those edible Dorito forks into the finest instant noodles in all the land.
Indeed. It’s all quite overwhelming. I guess the nub of my question comes down to why would you recommend one form of chemo over another? Is it largely driven by side effects, or does hitting different tumours in different ways tend to work better?
From this list of cancer drugs, interesting to note that Velcade (similar to AVA3996) is often given in combination with liposomal Doxorubicin. These first two may have been selected as options that complement each other well. Imagine (a few years and some hopefully successful trials later) having the best/safest two chemo drugs on the market, and them working together well in tandem…
Just airing something I’ve been musing here, and would appreciate thoughts from anyone who knows more than me (form an orderly queue please).
If the ultimate indicator for use of AVA6000 is any tumour with relatively up-regulated FAPa, then what will differentiate it from the other drugs in the PreCision pipeline, which will presumably also be applied to tumours with a concentration of the same target?
In the one sense, I wonder if this represents a risk, that the different PreCision drugs could cannibalise their own market, hence creating a need to be very careful to whom Avacta license other drugs in the pipeline, when, and under what terms. In another sense, it highlights the breadth of opportunity for each and every drug in the pipeline to hit the market, with a huge potential advantage to the first one. A dramatically improved safety profile for AVA6000 would likely not only allow it to take over and grow the doxorubicin market, but also perhaps take over market from other chemotherapy drugs in use.
Unless… and here’s what I need help to understand, it’s not just targeting to FAPa that determines applicability, but also whether different warheads work differently in different tumour types?
To the previous 2/3 posters this morning - obviously I was exaggerating, and did not mean to imply that you are nobody! Crack on, have a good day all.
Topped up another million-ish shares in the ISA today.
I’ve got a lot of confidence in the delivery and revenue growth here, even if the management have been a bit vague on some of the latest projects. Part of that is undoubtedly not giving away strategic advantage by telling the competition exactly what you’re going to do before you’ve launched it. But the growth numbers speak for themselves and the rate of deal delivery is strong.
I think the share price is just in the sweet spot now of being right on a mid-term support level, on a base supported by the 0.3p fundraise, the 0.5p warrants have now expired, and nobody’s talking about it. DYOR but I like it here.
Hi sitian,
Yes, I believe usual dose is c.60mg/m2 over six treatments, and that total is approximately the lifetime cumulative suggested dose, above which the probability of other complications, including mainly heart problems becomes unacceptable. First dose of 80mg/m2 was equiv to about 54mg/m2, so current dose is equiv to about 81mg/m2, I.e. 135% of the standard dose. I am not sure if they have said yet whether they still do 6 doses at this level or do fewer to stay under the max cumulative doxorubicin dose. Alastair stated in Q and A today though that the lifetime Dox dose need not necessarily apply to AVA6000 since it is targeted to the tumour, so I wouldn’t be surprised if they are going for the full 6 doses.
On assessment of tissue damage, unfortunately regular Dox causes side effects that are extremely apparent to the patient, eg hair loss, vomiting, nausea, sores around mouth/marks on hands etc. Look up the side effects of Doxorubicin for a humbling read. As well as blood and urine samples and biopsies, they will be closely monitoring side effects to check safety, which I assume is a reasonable proxy for off-target tissue damage, given they know all the usual side effects of Dox to look out for. I don’t think ultrasound would show up anything. Maybe that’s a technique they might use in a later phase to assess tumour size?
Marik & RAH posted a nice case on Twitter for what the 50% dose escalation might indicate about the side effects experienced by the first cohort:
https://twitter.com/rah00084/status/1489631807486279682?s=21&t=WG4js_b3ulJKpFbt8Rc-jg
Good luck with your research.
I am predicting grey suit. Sadly he seems to have pooh-poohed the shumper since returning to an office environment. Does it represent a symbolic turning of his back on the PI community that embraced his personal shumper brand before showering him with unabating buckets of **** for the LFT debacle? Or does he not give two hoots because he has more important things to worry about
Update this morning was fine. Cash to near end-Q1 at current rate - a fair bit of slack after phase 1a results for some deal-making, provided they prepare for success now, which they seem to be, according to Poirot’s digging into job adverts for new positions (paralegal seemingly to support deal-making, for notable example), and new appointments of senior advisors to help guide strategy.
All extremely positive language and indications on the trial progress. I wouldn’t say it’s “high-risk” like some - bear in mind TD’s conservative 10% chance of success for AVA6000 is to get it all the way to market. Each individual step on that journey, eg Phase 1a, carries a much lower risk. But it ain’t hatched until it’s official.
Although I see this was submitted in October 2021, so pretty quick overall!
Thanks for sharing. This comes from researchers at Leeds Uni, but sounds to my lay brain like the sort of thing Astrea Bioseparations might be working on. I wonder if there is some link?
Peer-reviewed academic papers tend to take ages from initial submission to publication, usually a year or two. Then they may be published online before the print version. The date will be when the print version comes out.
Ah I was wondering why the share price jumped the last couple days. Obvious now… Poirot’s back! Good to see you active again.
But sorry to hear about the rough few weeks… Hope things are on the up now. There is so much more to life than the markets, whether they be rough or smooth. Take care and stay well.