England, United Kingdom
Joined June 2013
- Tweets320
- Following184
- Followers355
- Likes5.4K
#AVCT
“Almost any small molecule can be introduced into this system.”
“And so there really isn’t a solid tumour that we can’t treat with a given pre|CISION medicine.”
Chris from the recent 6103 Spotlight about the potential and versatility of the pre|CISION platform.
And a little Friday musical interpretation. 🎶🦋
#AVCT
I thought Curtis was excellent in the latest R&D Spotlight. He explained some quite complex science really well. I was particularly interested in his discussion about what happens to FAP-positive fibroblasts with repeat dosing of AVA6103.
It reminded me of the informal discussion with Chris after the AGM, when she became particularly animated about the possibility of demonstrating FAP persistence and how that could be a “game changer” for the pre|CISION platform.
At BIO, Chris explained:
“The fibroblasts aren’t dying. And so the enzyme is still there.”
Now Curtis has presented some fascinating preclinical findings with AVA6103:
“Not only are fibroblasts actually maintained, but they are actually increasing with repeat dosing of AVA6103.”
He also described a “coordinated inflammatory and wound-healing response” and changes in pathways involved in DNA damage repair, cell cycle arrest and the surrounding tumour matrix.
The comparison with Enhertu, particularly the loss of HER2 expression, was also interesting.
I think these findings add another dimension to Chris’s comments at the AGM. She was very enthused about the possibilities back then - and used the words “game changer” twice. It is so important for 6103 and the platform.
#AVCT
Nice to see Florida Cancer Specialists & Research Institute (FCS) highlighting its involvement in AVA6103 in its ESMO 2026 news release.
FCS is one of the largest independent community oncology networks in the US, with an extensive clinical research programme.
Dr Judy Wang, Associate Director of Drug Development at FCS and an investigator in FOCUS-01, is named as a co-author of the AVA6103 poster.
The speed of enrolment in FOCUS-01 has been impressive, and access to patients is critical. It’s a huge positive to have such an established oncology research organisation involved in the trial.
flcancer.com/articles/fcs-dr…
Sandy Radford retweeted
ESMO all about resistance and degradation of target. @coughlin582 on point with latest “I.P.” declaration #AVCT
Sandy Radford retweeted
As #AVCT’s CEO explained during the interims, the majority incorrectly assume the delay on AVA6000 dealing is bad news.
It is quite the opposite: PFS takes a long time to collect (the longer, the better).
After all, this primary end point will decide approval for AVA6000.
Sandy Radford retweeted
The disclosure of AVA6207’s warhead (to sit alongside Exatecan) will take place on 19 November 2026.
Whilst we would not expect a partner to be announced in tandem with that disclosure the warhead choice should prove highly informative as to #AVCT’s AVA6207’s partner.
Very confident language from the company since the initial data was released on 16 September.
“Consistency”, “concordance”, “exceptional alignment”, “pretty much spot on” - and now “working in patients, exactly as modelled”.
#AVCT
#avct
“The controlled-release mechanism of our Next Gen pipeline with AVA6103 as the lead asset is now working in patients, exactly as modelled, and we are moving towards initial efficacy data in 2027.”
Chris Coughlin 30th September
Strengthen the balance sheet, strengthen the negotiating position.
#AVCT
TVR5 fully supports the #AVCT board’s strategy to protect the inherent value of the pipeline, given the strength of the AVA6103 data to date. We expect the board to close its first validating deal in Q4 2026, following this bolstering of the company’s negotiating position.
#AVCT
A nice little trip down memory lane for me.
“If those two inventions, the capping group and the linker, those two inventions, if it actually does what we think it’s going to do in patients, WATCH OUT!”
Proof of mechanism ✔️ The initial data released earlier this month marked an important milestone for the company.
Good recollection. Looking back Chris has mentioned gastric more than once:
#AVCT AGM 2025:
“Right now, our two favourites are pancreatic and gastric. Two places where topoisomerase 1 is used as a single agent and where we see very, very broad expression of FAP.”
Rx for BIOTECH podcast, April 2026:
“I’ve been asked the question, which do you think is the most likely? Well, if you look at Enhertu in gastric cancer… works really well in gastric cancer, and we have almost the exact same payload… So if I had to, if I had to pick one, I would probably say that gastric cancer is our most likely.”
You don't just add 7 new trial sites at some of the most prestigious oncology centers globally unless your trial is going well. Huge cost for this but even bigger validation = Green lights.
Gastric in focus and recalling CC comments from a previous event a year ago where she stated Gastric was her first indication pick at the time to see responses!
Very telling they have been telling us a lot about the progress with PDAC the likely hardest of the 6 indications to treat first....Have they cracked them all?
Well done AVCT #AVCT
mskcc.org/cancer-care/clinic…
Sandy Radford retweeted
Even if you take the position that their tech is yet to be proven, you should not fail to be impressed with their chutzpah. Going after pancreatic cancer and making head to head comparisons with Enhertu is a big counter to their sometimes dry scientific language.
#avct
Alex Spira summed up one of the constraints of ADCs at Science Day - the side effects can limit the dose and mean the MTD is reached at lower levels. He also made the point that a different approach is needed beyond the “typical antibody drug conjugates”, describing pre|CISION as a “unique entity and moiety”.
Step forward #AVCT
#AVCT
“The ability to deliver dose intensity and flexible administration is unique to preCISION® Next-Gen PDCs”
“Dose densification”
An important part of the AVA6103 trial design.
The #AVCT definition: the ability to pack more total payload into the same 12 weeks than would typically be possible with an ADC.
Dave’s point on Spotlight 16: AVA6103 is a small molecule, so it doesn’t have the extended PK of an ADC, “and it allows us to have quicker recover than an antibody.”
AVA6103 is being tested both Q3W and Q2W.
Equivalent payload dose. Q2W instead of Q3W means 50% more payload over 12 weeks in the gastric, pancreatic and colorectal cohorts.
More bounce to the ounce, so to speak.
Dave, Spotlight 16:
“And what that really means, to put it into simpler terms, is that over a given period of time, we can administer more drug. And so we’re able to give these closer together, which is how we achieve that higher dose intensity.”
“The world is our oyster.”
“Almost the sky is the limit.”
The Quattro is getting fired up.
#AVCT
🤖 Made with AI
It is clear to many #AVCT is about to go on a a run.
Why?
preCISION sits on the cusp of disclosing human data which, if confirmed, changes what’s possible with PDCs from every perspective: safety, efficacy, stability, cost and utility.
“It really doesn’t have a lot of limits”
Thanks RAH. This is an interesting bit of detail from R&D Spotlight 15 on the importance of the tumour acting as a “reservoir” for AVA6103, helping underpin its sustained-release mechanism. #AVCT
avacta.com/research-developm…
#AVCT
The “reservoir effect”.
Expect to hear a lot more about it.
However, I struggle with the analogy. What does a big artificial lake full of water have to do with AVA6103?
Many powerful cancer drugs work, but they also damage healthy tissue because they circulate freely. We all know this.
AVCT attaches a small peptide "mask" to the drug/warhead.
Think of the warhead as wearing this mask.
Whilst wearing the mask, the drug cannot enter (healthy) cells.
It is largely silent in the bloodstream (hence Avacta’s strap-line).
The lock is designed so that only one enzyme can remove the mask from the drug: FAP (fibroblast activation protein).
FAP sits on the surface of cancer-associated fibroblasts — support cells that wrap around most solid tumours (AVCT says this is true in about 90% of solid tumours, hence the massive addressable market).
Healthy tissues have far less FAP.
When the masked drug reaches the tumour, FAP ‘snips/cuts’ the peptide away.
The free drug is then released right NEXT TO the cancer cells.
What’s the “tumour reservoir concept” all about?
This is the extra twist with second generation tech AVA6103 (masked exatecan):
The “still-masked/locked” drug reaches the tumour quickly (peak levels are achieved in minutes, not a day later as with some antibody-drug conjugates).
The intact conjugate stays in the tumour for days (~5 days in pre-clinical/animal studies of AVA6103).
FAP keeps cutting the peptide over that time, so active drug is released in a sustained trickle inside the tumour.
Any active drug that leaks into blood is cleared fast (for AVA6103 pre-clinic the released exatecan was undetectable in plasma after about four hours).
Hence they refer to the tumour microenvironment as acting like a reservoir: it stores the locked form of the drug and slowly dispenses the active drug locally.
However, it’s an analogy which doesn’t chime with me. It doesn’t make the concept easier to understand for a lay investor imho.
I find it easier to think about it as a smoker with a cigarette.
Think of AVA6000 as a camel light. You get a hit of nicotine instantly.
First-generation AVA6000 is a simpler, faster-cleaving version of doxorubicin. It doesn’t need to be made to hang around quickly.
Smoke the cigarette. Get the nicotine hit. Need another hit, have another cigarette.
Normal/naked Exatecan is very different. It has a very short half life. About 9 hours.
Think of Extatecan like a 2cm long Marlborough red.
Really strong but upon lighting it, it’s gone after a drag.
Now think of the generation 2 (extended release) technology as acting like a nicotine patch. Not a 2cm Marlborough red.
A slow, controlled release.
The release is so controlled preCISION enables Exatecan to remain at “killing cancer concentrations” inside the tumour for days (~5 days in pre-clinic).
What does this mean?
More drug where the cancer is, less in heart, bone marrow, and the rest of the body.
In principle, this “nicotine patch concept” of AVA6103 means higher doses or more cycles become possible.
This is because release happens outside cells so neighbouring tumour cells (that do not express FAP) can still be killed (the “bystander effect”).
I.e. extra cellular. Outside the cells. Anything not inside a cell: blood, lymph, the tumour microenvironment. If the cell is a house, extracellular is the street and garden.
ADCs however rely on intercellular release (between cells). They therefore rely on a complex bystander effect with CAFs acting as the resistance mechanism, not an aid (as they are with preCISION).
Blood vessels, FAP-positive fibroblasts, and tumour cell nests sit close together, like cancerous scaffolding, which helps this effect.
Its turns the drug into a slow-release nicotine patch that keeps dosing while the rest of the body sees very little of the active drug.
This is “the reservoir effect”.
Proving in human gives access to ~90% of the solid tumour market.
Sandy Radford retweeted
#AVCT
Have been scrolling the AACR website and saw this:
“Pancreatic ductal adenocarcinoma (PDAC) is predicted to surpass colorectal cancer as the second leading cause of cancer death in the US in the next decade.
This dismal projection is largely due to late diagnosis— often after the cancer has spread to other organs.”
The 2nd leading cause of cancer death in the US.
Enhertu uses Deruxtecan as its warhead. Delivered via ADC.
Deruxtecan is a close derivative of Exatecan, but slightly less powerful.
As has been pointed out, when Enhertu was mid trial, its owners decided to put the drug into 25 pancreatic cancer patients.
The DESTINY trial.
25 pancreatic patients enrolled.
Confirmed Objective Response Rate (ORR): 1 out of 25 patients via investigator assessment.
The cohort was closed early such was its poor performance.
Remember Enhertu activates via HER2.
In the IHC 3+ subgroup (I.e. the highest HER2 expression) there was a 0% ORR.
Zero percent.
That’s how hard pancreatic cancer is to crack.
Enhertu failed, really quite miserably.
PDAC is the most common type of pancreatic cancer. It can grow anywhere in the pancreas.
The tumour microenvironment makes this worse.
Dense stroma and poor blood supply.
Cancer-associated fibroblasts (CAFs) further support the tumour. Like scaffolding.
Its dense stroma and fibroblasts have historically made it incredibly difficult to deliver drugs effectively to the primary tumour.
Recall Alex Spira from Science Day describing the stroma “like cement or straw” sat around the tumour. Thanks Sandy for the clip!
So, what if, your platform thrives in the very environment others fail in?
You’d probably take it to AACR Pancreatic to shout about it, wouldn’t you?
Sandy Radford retweeted
The deadline for this application was 6+ weeks after #AVCT first dosed AVA6103.
Both Q2W & Q3W dose escalations will have occurred in this period.
The clearest signal yet that AVA6103 is extending the release of Exatecan in human, just as it was designed.
Pharma on notice.
