Member Info for BuenaVista

On that usage of British/American English, I got told by my American colleagues to remove/reword "whizzing" on the global intranet site. It was an accidental mistake, honest guv.

American CEO and increasingly American management and the company is heading towards increasingly US interactions (FDA, trials, NASDAQ). CC will be deciding which version of English to use so it's understandable. Personally I don't like that sort of cultural imperialism, absolutely detested it in the company I worked in, which wasn't even an American HQ'ed company, when I had to use American spelling on UK intranet pages and was a minor factor in me leaving/retiring.

Anyway, this will be resolved one way or the other when we get taken over.

The FireFox update was about the newly added VPN feature.

A FireFox update on my PC always means I have to log into HL and reset my Watchlists so that I can view them when not logged in.

No they don't.

The links give pop-up boxes. I turned all pop-ups off in my FireFox settings some time ago (to stop ads popping up) but allowed HL pop-ups.

Can't remember when they stopped working as I now only use LSE for news. Anyway, I reset to blocking all pop-ups today and then allowed HL pop-ups but they don't appear.

There was a FireFox update this morning...

The HL website doesn't have any more news than LSE has on the AVCT Share News link.

As far as I can see the only thing HL gives me that I don't get elsewhere—and better—is the live share price spread.

And 'non-cdn sting agonists':

Non-CDN STING agonists are synthetic, non-nucleotide small molecules designed to activate the Stimulator of Interferon Genes (STING) pathway, overcoming limitations of cyclic dinucleotides (CDNs) like poor cellular permeability and metabolic instability. Examples include MSA-2, SNX281, and benzimidazole-based compounds, which are often orally available, systemic, or more stable for tumor-specific activation in immuno-oncology.

Key Non-CDN STING Agonists and Characteristics

• MSA-2: A prominent, orally available non-nucleotide STING agonist that mimics the structure of CDNs to trigger the STING receptor, offering a solution to the short half-life of traditional CDNs.

• SNX281: Developed by Silicon Therapeutics (now Roivant Sciences), this non-CDN agonist is in Phase I clinical trials for cancer immunotherapy.

• Benzimidazole derivatives: These represent a significant class of non-CDN agonists currently under investigation for treating infectious diseases, autoimmune disorders, and cancer.

• Advantages over CDNs: Unlike CDNs, which are generally polar and require intratumoral injection, non-CDN agonists are designed for improved cellular membrane permeability, better pharmacokinetic profiles, and systemic administration.

• Mechanism: They activate the same STING pathway as natural ligands, triggering type I interferon production to turn "cold" tumors into "hot" tumors, enhancing immune infiltration.

These molecules are crucial for reducing the toxicities associated with systemic delivery of early STING therapies and are generally designed for enhanced stability.

Continuing with a simple 'CDN agonists' query to Gemini:

Cyclic dinucleotides (CDNs) are potent STING (Stimulator of Interferon Genes) agonists that activate the innate immune system, inducing type I interferons and proinflammatory cytokines to fight tumors. While effective, natural CDNs (e.g., 2'3'-cGAMP) face challenges like low membrane permeability and stability. Modern approaches use, for example, InvivoGen's 2'3'-cGAMP for high-affinity STING activation.

Key CDN Agonist Information

• Examples: c-di-GMP, c-di-AMP, 3',3'-cGAMP, and 2',3'-cGAMP.

• Mechanism: They enter the cell and bind directly to the STING adaptor protein, activating the TBK1-IRF3 signaling pathway.

• Challenges: High polarity, rapid degradation, and poor cellular uptake often limit their, for example, intratumoral injection (as seen with ADU-S100).

• Overcoming Limitations: Strategies include chemical modification (phosphorothioate modifications) and, as shown on Nature Materials, specialized delivery vehicles like liposomes or nanoparticles to boost potency and tumor targeting.

• Clinical Status: Several analogs are in phase I/II trials, such as TAK-676 for advanced solid tumors.

For more information, feel free to ask about:

• Specific types of CDNs (natural vs. synthetic)

• Clinical trials involving CDN agonists

• Delivery methods to improve efficacy

STING agonists do seem an ideal warhead for pre|CISION:

Key Aspects of STING Agonists

• Anti-tumor Mechanism: STING agonists boost anti-tumor immune responses by promoting type I interferon secretion, increasing T-cell activation, and potentially transforming "cold" tumors (immune-inactive) into "hot" (immune-active) ones.

• Clinical Applications: They are being researched for cancer immunotherapy, often in combination with immune checkpoint inhibitors (e.g., PD-1 inhibitors) to treat resistant tumors.

• Administration & Challenges: While effective in preclinical studies, many STING agonists are limited to intratumoral injection due to toxicity risks, prompting research into targeted delivery methods like Antibody-Drug Conjugates (ADCs).

• Examples include Dazostinag disodium (TAK-676), IMSA101, MK-1454, ADU-S100 (MIW815), and non-CDN agonist MSA2.

Current Developments

• Overcoming Resistance: STING agonists show potential to overcome resistance to conventional immunotherapy.

• Development Status: Numerous agonists are in phase I/II clinical trials to evaluate safety, dosage, and tumor reduction efficacy.

• Novel Formulations: Research focuses on developing systemic (non-intratumoral) delivery systems to minimize toxicity and improve efficacy.

I thought m name sounded familiar.

Avacta announces new appointments to the Scientific Advisory Board of its Therapeutics Division | Avacta Therapeutics

https://avacta.com/avacta-announces-new-appointments-to-the-scientific-advisory-board-of-its-therapeutics-division/

06 Sep 2021

"Stéphane Champiat MD, PhD is a physician at the Gustave Roussy Cancer Center in Paris, where he focuses on the development of cancer therapeutics, in particular, new immunotherapies. He has been principal investigator or co-investigator of more than 50 Phase I clinical trials run by many of the world’s leading pharmaceutical and biotech companies. He is particularly involved in the coordination of the immunotherapy toxicity management program and the development of the intra-tumoral immunotherapy strategy at Gustave Roussy."

the rsi is currently 60.67, up from 58 at end of yesterday and down from just about touching 70 on tuesday when the share price had its recent peak of 80p or so.

anything below 50 and certainly by 40 or even 45 is looking like a good buying opportunity these past couple of months.

all can be thrown out of course by news, good or, god forbid, bad.

tiny url : ********************43fycc7x

CORRECTION

It was wrong of me to state "AVA6207 is a dual warhead of exatecan and an ATR inhibitor..." In the Q1 2026 Highlights, Company Outlook for 2026 section, it is stated that "Payload selection and clinical candidate selection in the Gen Three* pre|CISION® Dual Payload program (AVA6207) are expected in H2 2026. Updated in vitro and in vivo preclinical data will also be presented at the AACR Annual Congress on 21 April 2026."

PARP inhibitors are then still, at least in theory, in the running to be one of the dual warheads of AVA6207 but, if so, why was the AACR 2026 AVA6207 poster all about ATRis, with not a single mention of PARPis? Unless they are saving the (preferred?) PARPi data for the autumn AACR-NCI-EORTC conference? Maybe a lot of negotiating going on behind the scenes!

* So Avacta now have two separate Gen Three programs: AVA6207 — a PDC, and AVA7100 — an AffDC!

Repare Therapeutics was acquired by XenoTherapeutics in January of this year. XenoTherapeutics, Inc. is a Massachusetts-based 501(c)(3) research foundation focused on advancing xenotransplantation through scientific research, clinical development, and public education.

They have an incredibly annoying website: https://www.xenotx.org/

"By using genetically engineered pigs as a consistent, living donor source, we aim to make regenerative therapies more accessible, more reliable, and more responsive to patients’ needs."

LF, the whole biomedical world, from basic research through clinical development to treating patients in GP surgeries and hospital is truly the best of human endeavour, a global collaboration between people of all nations, races, creeds, etc., etc.

The scientists will stand in front of their poster for about 3 hours and talk about their work to anyone wandering past who shows an interest or has questions.

Our CEO usually does a video presentation to explain it all to shareholders. There was an Investor Meet Company video the other day which from the title seemed to be about the AVA6103 poster but I've not watched it yet so it might cover both posters.

That's American Merck (Merck & Co). The original Merck company was spilt in two, a consequence of WW2.

Interested board members might like to run these two queries on their favourite AI platform:

How many ATR inhibitors are there and who owns them?

Which of the ATR inhibitors are the most potent, especially using the GI50 metric?

From my running of these, AstraZeneca came out as having an early but not the most potent ATRi. The only other major companies with the clout to finance a deal were Merck KGaA and Bayer. I'd be interested if board members can come up with any further inhibitors and big farmers.

Yes, it's certainly true that investigational drugs can be used in experiments. I'm not saying there has to be an agreement with the owner now but that there will need to be an agreement should an ATRi be taken to market as part of AVA6207.

I'm on my mobile at the moment so research is even slower and more difficult than putting together a coherent argument but... My understanding of the AVA6207 poster is that only ATRis and no PARPis get a mention. Does this mean that AVA6207 will contain an ATRi and NOT a PARPi? I think that's a fair assumption.

So when would Avacta need to announce a tie-up? When there is an agreement, a MoU or a deal with money involved. When will that be? Maybe when the owner of the chosen ATRi likes the data?

I find it very odd that Avacta are totally ignoring the existence of the ICR poster presentation, especially since the work was obviously funded by Avacta, starting some time ago.

Or is it?..

So, Avacta have been interested in doxorubicin coadministered with ATR inhibitors... AVA6207 is a dual warhead of exatecan and an ATR inhibitor...

My guess is that that ATRi might be one of the ones in Banerji's poster presentation, all three of which are in patent — two (M4344, gartisertib and VE822, berzosertib) owned by and licensed to Merck KGaA (a German company) respectively and the other (BAY1895344, elimusertib) owned by Bayer (also German) — and in clinical development.

I'm guessing this because Gemini says:

"No ATR (Ataxia Telangiectasia and Rad3-related) inhibitors have received regulatory approval (FDA or otherwise) as of early 2026. While they are highly promising agents for treating cancers with DNA repair deficiencies (such as ATM or BRCA mutations), they are still currently in Phase I/II clinical trials, with some advanced development projects recently discontinued."

All of which means the ATRi in AVA6207 MUST be owned by a farmer so there HAS TO BE some sort of agreement, licensing or partnering.

So the latest concern of the dim trolls is that if a small amount of cytotoxin works, then a large amount concentrated in a tumor... may not work? Is that these clowns' latest thesis?

🤡🤡😂

Clarification of "The GI50s in the two PDAC cell lines are different! 66.5±16.3nM and 58±21.4nM respectively. Odd?"

By this I meant the results in the image and the results in the abstract are different, not that the results are different between the two PDAC cell lines – that's to be expected.