Member Info for BuenaVista

Yep, it's legit and works whereas tiny url is now masked (for some unfathomable reason).

********************45mtm4at

A cytotoxic platform that is exquisitely targetted to the site of the tumour with minimal off-target toxicity is the holy grail of chemo.

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The "holy grail of chemotherapy" is not a specific treatment but rather a metaphorical term in cancer research that refers to an ideal, universal solution for cancer. This "holy grail" generally encompasses one or more of the following concepts:

1 - A universal cure: A single treatment or pill that is effective against all types of cancer, regardless of the tumor's origin or stage.

2 - Selective targeting: A therapy that specifically eradicates cancer cells while leaving healthy, normal cells unharmed, thus minimizing the severe side effects associated with traditional treatments like chemotherapy and radiation.

3 - Early detection: A simple, reliable test (such as a blood test or "liquid biopsy") that can accurately detect the presence of cancer at its earliest stages, often before symptoms appear, when it is most curable.

4 - Overcoming drug resistance: A strategy or treatment that can prevent cancer cells from evolving and developing resistance to therapies, which is a major challenge in long-term cancer control.

Researchers at institutions like City of Hope have developed promising molecules, such as AOH1996, that show "holy grail" potential in preclinical research by targeting a protein common to many cancers (PCNA) without harming healthy cells. Clinical trials for such innovations are ongoing, bringing the medical community closer to the dream of highly effective, less toxic cancer care.

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1 - Good for up to 90% of solid tumours (but 100% of epithelial tumours)?

2 - This is what the pre|CISION platform does - specific for FAP

3 - Could Avacta exploit this with staining dyes rather than cytotoxins?

4 - Will be achieved with dual payloads?

She was pleased because the half-life of exatecan is under 10 hours and AVA6103 vastly extends that.

End of discourse.

Now crawl back into your hole.

ToucanOfIrony wrote: "the amigos (3 or more) seldom abuse or wish harm on the Pom Pom girls"

🤣🤣🤣

"I don’t think anyone is worried about half life, because 6103 has sorted that."

@ToucanOfDoom, you do realize, do you not, that different chemicals - drugs, prodrugs or neither - have different half-lives?

It's worth considering why and when Pfizer bought Seagen's ADC tech for $34bn.

https://www.google.com/search?q=Why+did+Pfizer+buy+Seagen+and+what+stage+of+development+was+Seagen%27s+tech+at+when+bought%3F

Seagen was more much advanced than Avacta currently is with 4 marketted products and a pipeline of 38 programs in clinical development. On the other hand, there are manufacturing and toxicity/side-effects problems and high costs with ADCs that are so far absent or very largely absent with Avacta's pre|CISION PDC tech. As others have said, if the data for AVA6000 continues to be good and is then supported by AVA6103 clinical data that would make Avacta a very tempting target, and if the platform is further proven by strong early AVA6207 data then we'd surely be talking about something comparable to the Seagen buyout rather than the $8bn or $20bn for the first one or two proofs of pre|CISION working. Add in AffDCs clinically proven to be safe and clinically effective and we're laughing, maybe $50bn.

(All Avacta figures plucked out of thin air by me)

My hope though is that we go down the licensing route. Whichever route we take, my strategy would be very similar to cj's with recouping of invested capital plus more (to go into high interest paying investments) with the remaining shares riding for free for a while, awaiting a buyout or chunky Avacta dividends.

I've done it now. I've probably cursed my investment...

It looks like this page needs updating with just the Phase 1b details and indications:

A Phase 1a Study of AVA6000 in People with Solid Tumors

https://www.mskcc.org/cancer-care/clinical-trials/22-428

Contact William Tap @mskcc.org ?

I was just perplexed how a self-professed nurse botherer got himself invited to your granddaughter's school Christmas dinner.

Well I suppose we could ask whether "Before proceeding to IND-enabling studies, however, further work, which is planned for STTR Phase II, will be required in order to: (1) improve prodrug half-life in vivo" ( https://web.archive.org/web/20240716033941/https://grantome.com/grant/NIH/R42-CA156930-02 ) was addressed, actioned and achieved. ...Or whether we need to go back to the drawing board and redesign AVA6000 so that it has a longer half-life.

I do like the IMC 'Ask a question for the company to ignore' interface. Very easy to enter, review, and edit.

What are your best questions so far?

Put them into Google and you'll find that each have only 2 out of the 3 parameters (major, amount, target) right, meaning that it's all nonsense, probably AI-generated like the rest of Unicorno's 'you'll all be rich soon' postings.

For instance, Pfizer acquired Seagen for $43bn and Nona Biosciences for $53 million upfront, with the potential for up to a further $1.05bn.

https://www.bioprocessintl.com/deal-making/done-and-dusted-pfizer-completes-43bn-seagen-deal

I thought he was low when it was just nurses.

It can't be the definitive data because the first doses the patients had weren't a year ago, so data for secondary outcome measurements are not complete yet. Hopefully PFS is still open and increasing.

VS wrote: "If CC so much as hints "further data" we'll all be killed in the stampede."

This will be interim data, so there will be further data as there are Secondary Outcome Measures that go on for up to a year - longer for PFS and anything else that isn't resolved within a year.

We all have to believe something. I believe I'll have another drink.

These won't be comprehensive lists - they are, afterall AI-generated - and they don't include ones that have failed during in-house preclinical development nor newly patented ones that are in preclinical development but will fail.

The warheads conjugated to antibodies in ADCs that are either approved or in clinical trials for epithelial cancers fall into several major classes, primarily tubulin inhibitors and DNA-damaging agents:

Approved ADCs in Epithelial Cancers

• DM1 (maytansine derivative, a tubulin inhibitor): conjugated to trastuzumab emtansine (Kadcyla) for HER2-positive breast cancer

• DM4 (maytansine derivative, a tubulin inhibitor): conjugated to mirvetuximab soravtansine (Elahere) for folate receptor alpha-positive ovarian cancer

• MMAE (monomethyl auristatin E, a tubulin inhibitor): conjugated to enfortumab vedotin (Padcev) for urothelial cancer and tisotumab vedotin (Tivdak) for cervical cancer. It is also the payload for the China-approved disitamab vedotin (Aidixi) for gastric/urothelial cancers

• SN-38 (topoisomerase I inhibitor, active metabolite of irinotecan): conjugated to sacituzumab govitecan (Trodelvy) for triple-negative and HR+/HER2- breast cancer, and urothelial cancer

• DXd (deruxtecan, a topoisomerase I inhibitor): conjugated to trastuzumab deruxtecan (Enhertu) for HER2-positive/low breast, gastric, and non-small cell lung cancer (NSCLC). It is also the payload for datopotamab deruxtecan (Datroway) for breast and lung cancer

• IRDye 700DX (photosensitizer): conjugated to cetuximab sarotalocan (Akalux) for head and neck squamous cell carcinoma (approved in Japan)

• Belotecan-derivative (topoisomerase I inhibitor): conjugated to sacituzumab tirumotecan (Jiataile, China approved) for EGFR-mutant NSCLC

• SHR9265 (exatecan derivative, a topoisomerase I inhibitor): conjugated to trastuzumab rezetecan (China approved) for NSCLC

• Duostatin 5 (tubulin inhibitor): conjugated to trastuzumab botidotin (China approved) for HER2+ breast cancer

Warheads in Clinical Trials for Epithelial Cancers

• Duocarmycin derivative (DNA alkylator): conjugated to trastuzumab duocarmazine (SYD985), in trials for HER2-positive breast cancer

• PBD dimer (pyrrolobenzodiazepine, a DNA cross-linker): ADCs using PBD payloads like tesirine are in trials for solid tumors (e.g., TR1801-ADC for c-Met-expressing tumors, which include NSCLC)

• Hemiasterlin derivative (tubulin inhibitor): conjugated to STRO-002 for ovarian and endometrial cancers

• Eribulin derivative (tubulin inhibitor): conjugated to MORAb-202 for ovarian, breast, and lung cancers

And for clarification about exatecan's "insufficient efficacy compared to approved analogs":

Clinical trials of Exatecan (DX-8951f) as a single agent were discontinued primarily due to a combination of unmanageable toxicity and insufficient efficacy in human trials, despite promising preclinical data. The drug's high potency led to significant systemic side effects, making it difficult to establish a safe and effective dose (therapeutic window).

Reasons for Discontinuation

Exatecan is a potent topoisomerase I inhibitor. While preclinical studies showed it to be more effective at inducing DNA damage and apoptosis than topotecan or the active metabolite of irinotecan (SN-38) in cancer cell lines, this high potency translated into dose-limiting toxicities when administered to patients. The main issues that led to its discontinuation were:

• Dose-Limiting Toxicity (DLT): The primary DLT observed across multiple Phase I and II studies was severe, reversible myelosuppression (low blood counts), specifically neutropenia and thrombocytopenia. Non-hematological toxicities included fatigue, nausea, and vomiting.

• Insufficient Efficacy as a Single Agent: In various Phase II trials, such as those for advanced non-small cell lung cancer (NSCLC) and soft tissue sarcoma, exatecan demonstrated only limited or no objective responses. A trial for soft tissue sarcoma was stopped early due to a lack of activity.

• Narrow Therapeutic Window: The systemic toxicities occurred at doses where the anti-tumor activity was modest or non-existent in certain cancer types, meaning a safe and effective dose could not be consistently identified for a broad range of cancers.

Comparison to Approved Analogs

Exatecan did not show superior clinical efficacy compared to approved analogs like topotecan and irinotecan in the context of its systemic administration, primarily because its severe toxicity profile prevented the use of optimal therapeutic doses in humans.

• Topotecan and irinotecan (which is a prodrug converted to SN-38) were approved because they demonstrated manageable safety profiles and consistent clinical benefit in specific indications (e.g., ovarian and small-cell lung cancer for topotecan; colorectal cancer for irinotecan).

• While exatecan is a more potent TOP1 inhibitor biochemically, this potency was a disadvantage in free-drug form in the clinic due to widespread off-target toxicity to healthy, rapidly dividing cells.

The development of exatecan as a free drug was halted, but its potent antineoplastic properties have been successfully leveraged by reformulating it into targeted drug delivery systems, most notably as the payload in the highly successful antibody-drug conjugate trastuzumab deruxtecan (Enhertu®). This approach delivers the drug directly to cancer cells, minimizing systemic toxicity and realizing its high potency effectively.

Here are some of the 'fallen angel' drugs:

Several small molecule cytotoxins and related targeted agents have been investigated in clinical trials for epithelial cancers but were ultimately discontinued due to unacceptable or unmanageable toxicity that prevented them from progressing to registration. These compounds include:

• Maytansine: This highly potent tubulin inhibitor showed dramatic in vitro activity but failed in early-phase (Phase I and II) human clinical trials for diverse cancers, including likely epithelial types, due to systemic toxicities such as neuropathy, diarrhea, and weakness, which limited its therapeutic window. Its derivatives are now used as payloads in antibody-drug conjugates (ADCs) to enable targeted delivery and reduce systemic exposure.

• Exatecan (DX-8951f): A water-soluble camptothecin analog (topoisomerase I inhibitor) that entered clinical trials but was discontinued, mainly due to unmanageable toxicity and insufficient efficacy compared to approved analogs like topotecan and irinotecan.

• Lurtotecan (GCS-100): Another camptothecin analog that was tested in clinical trials (e.g., for ovarian cancer) but eventually discontinued due to dose-limiting toxicities and lack of significant benefit.

• Sinotecan: This camptothecin derivative also faced similar issues with unmanageable toxicity in clinical trials, leading to its discontinuation.

• AZD1480: A small molecule Janus kinase (JAK) inhibitor that reached clinical trials for solid tumors, including head and neck squamous cell carcinoma (HNSCC, an epithelial cancer), but its development was halted due to severe neurotoxicity.

• RB 6145: A nitroheterocyclic hypoxic cytotoxin that showed promise in preclinical studies but proved too toxic in animal models to warrant progression to clinical development.

• Streptonigrin and Lavendamycin: These natural product quinones exhibited potent in vitro anticancer activity but were found to be too toxic for systemic clinical use.

The inherent systemic toxicity of such potent small molecules often limits their therapeutic index when administered unconjugated, leading to the development of targeted delivery methods like antibody-drug conjugates (ADCs) to improve specificity and safety.