Thread by @MylesMcNulty

I came to appreciate long ago that AIM is an inefficient and irrational market.

But the share price of @avacta this week takes the biscuit. Following Monday's RNS, I was convinced we'd be at ATHs by now.

My explanation for what I think the market is missing on #AVCT ⬇️

1/25

https://twitter.com/MylesMcNulty/status/1465219470310400002

On Monday, #AVCT announced that it had received FDA approval for its Investigational New Drug ('IND') application, to expand its Phase I clinical trial for AVA6000, into trial sites in the US.

The timing of the submission and the length of review are critical.

2/25

The FDA has a 30-day review and turnaround time. Given #AVCT announced the approval this Monday, owing to LSE disclosure laws we must assume it received the approval sometime between Friday and Sunday.

Give a few days for post / admin / comms delays, and we can assume...

3/25

...that #AVCT submitted the IND application around 22nd-26th October.

The 1st patient in cohort 1 ('C1') at the Royal Marsden was dosed on 11 August. Subsequent dosings are done every three weeks.

Thus the first patient would have received their 4th dose on 13th October.

4/25

Now, a key point to consider in the IND Filing (thanks to @BigBiteNow for highlighting on Monday):

"The IND application must contain... any previous experience with the drug in humans (often foreign use)."

For #AVCT's AVA6K, that includes the...

5/25

fda.gov/drugs/types-ap…

...already-dosed UK patients.

So the FDA gave its approval to expand the P1 trial into the US, after having seen the data of - at the very minimum - one patient being dosed at least four times.

Two more points to consider.

1) C1 patients are being dosed at 90% of...

6/25

...normal doxorubicin dosing level.

2) At the time of IND submission, three hospitals in the UK were already recruiting.

clinicaltrials.gov/ct2/show/NCT04…

So what can we take from this?

Firstly, that recruitment in the US would be for subsequent cohorts - with the required...

7/25

...three patients for C1 already recruited by the UK hospitals (this was confirmed in Monday's RNS).

Secondly, that the FDA considered the data from the patients dosed in C1, and evidently liked what it saw.

C2 can only start once the third patient in C1 has had their...

8/25

...third dose, and then had a 21 day observation period.

We do not know when the third patient in C1 had their first dose, and so cannot precisely say when dose escalation / commencement of C2 may be.

But from the info in the public domain, it now seems pretty nailed on.

9/25

C2 will be receiving doses of AVA6000 that may be in the region of 50% more potent than standard-dox.

So what does that mean? It means that #AVCT pre CISION platform is - at least to some extent with doxorubicin - working.

It means that the initial dose level has a...

10/25

...better safety profile than standard dox, a drug that is already generated annual revenues of ~$1bn.

Of course, we have no idea how much 'safer' / how much more 'targeted' AVA6000 is than standard dox, at this stage. And unforeseen side-effects may yet flare up.

11/25

But fundamentally, dose escalation entails that an improvement in the safety profile of standard doxorubicin has been made.

There are those who have digested the info in the public domain, and positioned already. And there will be those who will wait on DE confirmation...

12/25

...before taking a position.

Hopefully, @avacta #AVCT gives an explanation (and perhaps a sliver of data) on HOW/WHY DE has been granted by the regulatory body - as the market clearly doesn't seem to grasp the implications yet.

13/25

There are numerous types of targeted cancer therapy.

The closest to what #AVCT is attempting with pre CISION (and even more so, the TMAC platform) are antibody-drug conjugates ('ADC').

An ADC is a molecule consisting of a monoclonal...

14/25

cancer.gov/about-cancer/t…

...antibody ('mAb') linked to several warheads (e.g. a chemo). Very broadly, the mAb takes the inert warheads to a tumor cell, enters via endocytosis, where the warheads are released, to destroy the tumor cell.

There have been many issues with...

15/25

adcreview.com/the-review/ant…

...ADCs to date, not least severe side-effects.

Having gone through much preclinical and clinical data, I haven't found anything that remotely resembles #AVCT's pre CISION (at least, the data generated in preclinical mouse studies).

Assuming the best case: preclinical...

16/25

...data are replicated in man.

At a tumor/heart ratio of 18:1, THEORETICALLY a patient could receive pro-doxorubicin that was 6 TIMES as powerful as the dox that is currently used, but with a reduction in cardiotoxicity by two thirds.

17/25

https://twitter.com/MylesMcNulty/status/1455245990492098568

As the pre CISION linker is a platform tech, #AVCT believes that - provided it works for doxorubicin, which as I have tried to point out, already looks probable - it could be used on more than a dozen other chemotherapies currently on the market, to drastically improve...

18/25

...their safety profiles.

Provided that cost of manufacture of pre CISION pro-chemotherapies isn't significantly more than standard chemotherapies - why wouldn't pre CISION prodrugs rapidly displace standard chemos from the global market?

19/25

globenewswire.com/en/news-releas…

The STANDARD chemo market is forecast to reach $74bn per annum within five years. But, as #AVCT itself has stated, a working pre CISION platform could multiply that market - MORE patients would be eligible for chemo, and ALL patients could endure more doses.

20/25

Back to ADCs, and their relevance in this thread to #AVCT and its current AVA6K trial.

Last year, @AstraZeneca #AZN signed a $6bn ($1bn of which was upfront) collaboration agreement with Daiichi Sankyo, to develop and commercialize DS's new ADC.

21/25

astrazeneca.com/media-centre/p…

At the time of the deal, the ADC in question - named DS-1062 - was in the middle of Phase I trials.

The same as #AVCT's AVA6K.

Also last year, Boehringer Ingelheim acquired NBE-Therapeutics for $1.5bn. NBE was only several months into a Phase 1 trial for its first ADC.

22/25

And also last year, Merck acquired VelosBio for $2.8bn. VB had completed a Phase 1 for its first ADC, but hadn't even started P2.

Looking at more advanced ADCs:

@GileadSciences $GILD acquired Immunomedics for $21bn last year. Immuno had just...

23/25

fiercebiotech.com/biotech/boehri…

...had its first ADC authorized by the FDA. It had so far racked up sales of only $20m, before $GILD swooped in. It valued Immunomedics at over 5x peak sales of $4bn (estimated to be reached in 2029!).

24/25

cen.acs.org/pharmaceutical…

Precedent is there for #AVCT to be taken out for $ billions in the near term.

The bull case thesis is that pre CISION prodrugs COULD be more targeted (so could be made more potent), cheaper, and are based on already widely used, successful drugs.

More valuable than ADCs?

25/25