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I know it's perhaps a crazy idea, but maybe the shareholder presentations are prepared well in advance rather than on the day?

I know it's perhaps a crazy idea, but maybe the shareholder presentations are prepared well in advance rather than on the day?

That was followed 8 days later by this: https://avacta.com/esmo-poster-data-video-presentation-by-chris-coughlin/

This year the two conferences are back-to-back rather than having a month between them, so whether we get one or two explainers is anyone's guess.

Regular abstracts for the main ESMO Congress 2025 were published online on October 13, 2025, at 00:05 CEST and Avacta's for the Tap poster has been made available on this BB. Last year, Avacta didn't provide any RNS with details about the poster until the Monday after the Saturday presentation.

https://www.lse.co.uk/rns/AVCT/avacta-reported-updated-phase-1-data-of-ava6000-3pl7ovwfilmpzie.html

So, same again this year I'd guess.

@ArchBishopHolmes

"Pipeline prioritization with workforce and cost reduction initiatives

• Caribou is prioritizing its lead oncology programs, CB-010 and CB-011. Caribou is discontinuing the GALLOP Phase 1 trial of CB-010 for lupus prior to dosing the first patient. Caribou is also discontinuing the AMpLify Phase 1 clinical trial of CB-012 for relapsed or refractory acute myeloid leukemia (AML) as additional data would be needed to advance this program, taking time and resources that can be dedicated to CB-010 and CB-011. Patients treated in the AMpLify Phase 1 trial will continue to be followed as part of the company’s long-term follow up study. Additionally, the company is discontinuing preclinical research.

• The company is reducing its workforce by approximately 32%. Cash payments resulting from the reduction in force and strategic pipeline prioritization are estimated to be $2.5 to $3.5 million.

• These changes are expected to extend Caribou’s cash runway by one year, funding the company’s current operating plan into H2 2027, compared to into H2 2026 as previously reported."

https://investor.cariboubio.com/news-releases/news-release-details/caribou-biosciences-announces-strategic-pipeline-prioritization

I should just add that for a Phase 1a trial, "assess treatment efficacy" isn't concerned with how well it works (with a statistically invalid 3 patients) so much as whether it works at all. As the progress of the 1st cohort has been reported patient by patient, it is highly likely that the DSMB will recommend progress to the next cohort and that may well already be baked into the share price. If the share price does rise on a positive recommendation by the DSMB, will that be a rerate or a spike? It's up to each investor/trader to choose, and act accordingly.

What's the beef here? A DSMB is a DSMB. There's no mystery about it. It is a requirement for a trial. Anyone can find out what it is. I was going to get the Wiki entry for it but just typing in 'data safety monitoring board' returned this, and more:

"A Data Safety Monitoring Board (DSMB) is an independent group of experts who monitor ongoing clinical trials to ensure patient safety and assess treatment efficacy. The DSMB reviews accumulated trial data, such as adverse effects and the progress of the study, and provides recommendations to the trial sponsor on whether the trial should continue, be modified, or be stopped early due to safety concerns or if the research question has been answered."

The DSMB will review the data, assess the safety to patients and either recommend progression to the next cohort or not. Whether progression to the 2nd of a possible four cohorts will lead to a rerating of the share price and consequent increase in Mcap is up to the market, taking into account many aspects concerning the science and funding.

I gather that it is intended that there will be (up to) four cohorts in Phase 1a, slated to finish in January 2027 - https://clinicaltrials.gov/study/NCT06786533 - which can only be a guestimate given the exploratory nature of Phase 1. Also surely more than one pediatric cohort will be needed as well now? Does Hemogenyx have funds to complete Phase 1a? Will there be a Phase 1b dose expansion?

Looking longterm, when do you think HG-CT-1 will receive regulatory approval? - What is the company's plan? I assume that, it being the way of clinical development for small biopharma companies, a lot more funding will be required in order to get there. Early days still, I know, but are plans for that funding in place already?

The way I understand it Bella: a buyer wants to do a worked order, the ?broker buys from sellers, only the sells show in the record, consequently the price drops, when the order is completed the buyer's whole trade is declared. Ore watt?

Older baron, watt is wrong with you're pee sea or eye pad or watt ever it is ewe use?

Well Derek, let's just wait until Prof Eggy has given it the once over and approved it.

If size were a problem then two dual payload drugs, each covering a key resistance mechanism of DNA damage repair as well as exatecan, could be given. That would have have greater flexibility of use (2 different drugs rather than 1 & 1+) in this case although there may be cases where three-in-one may be preferable. See? There are solutions if problems are talked through.

All of these are 'small molecules', about the same size as dox and EXd, nothing like the size of antibodies.

Possibility of a triple payload drug - why not?

ATR inhibitors

Ataxia telangiectasia and Rad3-related (ATR) kinase is critical for handling replication stress. Tumors that become resistant to PARPi can become addicted to the ATR pathway.

• Ceralasertib (AZD6738): This ATR inhibitor is being tested in combination with olaparib in patients with PARPi-resistant ovarian cancer and is primarily in Phase 2 and Phase 3 clinical trials. It is owned by the pharmaceutical company AstraZeneca.

• Camonsertib (RP-3500): This highly selective ATR inhibitor shows activity in PARPi-resistant tumors with specific DNA damage mutations. As of late 2024 and early 2025, it is in Phase 1/2 and Phase 2 clinical trials for various solid tumors. The global rights are owned by the Canadian-American biotechnology company Repare Therapeutics.

Pfizer, etc. may have their own candidates in their labs but a partnership with AstraZeneca has definite posibilities.

However, talazoparib is significantly more potent at trapping PARP1 on DNA than other clinical inhibitors, estimated to be up to 100 times stronger than niraparib, olaparib, and rucaparib.

The global rights to the PARP inhibitor talazoparib (Talzenna) are owned by Pfizer. In the United States, the primary patents protecting talazoparib (Talzenna) are set to expire on 20 October 2031. This date is also the estimated earliest date for generic entry into the market. It is important to note that a single drug can be covered by multiple patents with different expiration dates. Talazoparib has additional patents covering different aspects of the drug, but the 2031 date relates to the core drug substance and product. The patents covering the drug's use for specific indications may expire earlier.

So if the other payload is a PARP inhibitor, maybe a partnership with AstraZeneca, Pfizer, or...

Zero value. Binned

ToucanOfDoom, if you are concerned about that, Google 'does exatecan interfere with DNA'.

🙄🤡

PARP inhibitors seem to be the only marketted drugs that inhibit a 'key resistance mechanism of DNA damage repair' and of the four drugs approved by the FDA as of 20 January 2025, olaparib (Lynparza ) is the biggest seller and will be the first off patent - core compound patent expired in March 2024, followed by its use patents in 2025.

AstraZeneca is the company with the IP following its acquisition of the original developer, KuDOS Pharmaceuticals on 23 December 2005 for $210m (£120m).

So... do topoisomerase 1 inhibitors and PARP inhibitors work in combination?

AI Overview

Yes, topoisomerase 1 (TOP1) inhibitors and PARP inhibitors can work together synergistically, with preclinical studies showing enhanced cell death in various cancers. However, the combination is challenging in clinical settings due to significant side effects, particularly overlapping myelosuppression, which often requires dose reductions of both drugs. Strategies like using intermittent or "gapped" dosing schedules and tumor-targeted TOP1 inhibitors are being investigated to improve tolerability.

How they work together

• DNA damage and repair: TOP1 inhibitors trap TOP1 on DNA, creating a lesion that can stall replication forks and lead to double-strand breaks.

• PARP's role: PARP is involved in repairing single-strand breaks, which are the initial damage caused by TOP1 inhibitors.

• Synergistic effect: By inhibiting PARP, the PARP inhibitor prevents the repair of these single-strand breaks, allowing them to persist and convert into more lethal double-strand breaks during DNA replication. This leads to increased cell death in tumor cells.

Challenges and solutions

• Overlapping toxicity: Both drug classes can cause myelosuppression (bone marrow suppression), which limits the dose that can be given together.

• Intermittent dosing: Some studies use a "gapped-schedule," where a tumor-targeted TOP1 inhibitor is given first, followed by a gap to clear it from normal tissues before administering the PARP inhibitor. This helps manage toxicity while still allowing the two drugs to work together.

• Tumor-targeted delivery: Using a TOP1 inhibitor that is targeted to the tumor can reduce systemic exposure and side effects, making the combination more tolerable.

Dive deeper in AI Mode via https://www.google.com/search?q=do+topoisomerase+1+inhibitors+and+PARP+inhibitors+work+in+combination

The therapeutic index of a drug is the ratio of the dose that exerts toxicity in 50% of the population (TD50) to the dose that exerts a therapeutic or effective response (ED50) in 50% of the population (TI=TD50 / ED50). Therapeutic index can also be derived from the ratio of the lethal, instead of toxic, dose in 50% of the population (LD50) that is measured in animal studies

https://pharmacologycanada.org/Therapeutic-Index

The term represents the safety margin of a particular drug for clinical use, as high therapeutic index values indicate a wide margin between effective and toxic doses

So Eggy, did you read my response to Touk that addressed exactly the point you raised ("Interesting that the summary comments on the distinctly different Pharmacokinetics of standard Dox and FAP-Dox.")

Doxorubicin released from AVA6000 acts exactly the same way as traditional doxorubicin but, because it is far more dilute, it doesn't cause the same severity of side effects FOR AN EFFECTIVE CONCENTRATION AT THE SITE OF THE TUMOUR which is, as you say, 100x the concentration in the blood/plasma. Why do YOU need to know what that concentration in the tumour is? Are you capable of discerning whether a concentration of x is good or bad?