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That Avacta are developimg TWO lines of dual payload pre|CISION drugs when they don't have funds to carry faridox, let alone AVA6103, through the clinic strongly suggests that funding of one sort or another is coming ...er, shortly.

Look out for the blackcurrant-marmite combo flavour. Enormous health benefits but probably not going to be everyone's favourite.

Bella, that's the long way of saying "We have broad patent protection for this latest iteration of our core IP."

MMAE and the oldest PARPi are out of patent. As far as I can make out, the other PARPi's, including the by far the most potent one, and all ATRi's are still under patent. Whether Avacta is working with a big farmer on these is a moot point.

I prefer this version of the news release

I think these are fundamentally inferior to Avacta's dual warheads because they have two warheads attached to the antibody with no tumour-specific cleavable linker.

Written by AI, consumed by dimwits.😂💯👍👏🤷🏼‍♂️

Https://www.google.com/search?q=ELN+2022+criteria.+{Dohner+et+al.%2C+2022+%2329518}

Https://clinicaltrials.gov/study/NCT06786533

Primary Outcome Measures

1. Outcome Measure: Determine the safety of HG-CT-1 cells based on the proportion of subjects infused with HG-CT-1 who experience a DLT. Measure Description: Occurrence of dose-limiting toxicities related to HG-CT-1. First-in-human study with unknown safety of infusion of HG-CT-1. Time Frame: From the time of HG-CT-1 infusion until Day 28

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Secondary Outcome Measures

1. Outcome Measure: Estimate the efficacy of HG-CT-1 cells as defined by clinical response according to established criteria for AML. Measure Description: Proportion of subjects with response, according to ELN 2022 criteria. {Dohner et al., 2022 #29518}. To demonstrate the anti-AML activity of HG-CT-1. Time Frame: Day 14, Day 28, Month 3, Month 6 and Month 12.

2. Outcome Measure: Estimate the Overall Survival (OS). Measure Description: Proportion of subjects alive at 6 months and one year. To demonstrate effect on disease biology and prognosis (compared to historical expectations). Time Frame: At 6 months and 1 year.

3. Outcome Measure: Estimate the progression-free survival (PFS). Measure Description: Proportion of subjects alive without progression at 6 months and one year. To demonstrate durability of anti-AML effect. Time Frame: At 6 months and 1 year.

4. Outcome Measure: Estimate the Duration of response (DOR). Measure Description: Proportion of subjects with response who remain alive and without progression at 6 months and at one year. To demonstrate durability of anti-AML effect. Time Frame: At 6 months and 1 year.

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Four planned adult cohorts. First cohort completed.

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So how far has the study progressed?

only a ******** would know that

Don't bother replying eggy. It's clear you're out and in FUD mode looking to spook investors.

No integrity, no credibility, everyone is onto you. It's pathetic really.

Eggy wrote| "Bella, can you name me a single tumour type (where Dox is its usual standard treatment) where AVA6000 Dox has shown itself to be clinically superior?"

Eggy, can you name me a single tumour type (where Dox is its usual standard treatment) where AVA6000 Dox hasn't shown itself to be clinically superior?

B2H wrote: "Thus allowing full dosage to be restored, - resulting in more efficacy. ...presumably. 🤔"

Exatecan itself can't be given neat, so weaker Top1 inhibitors have been used - win 1

I'd guess that if Top1i and PARPi are:

• given at the same time then the first pass effecct will cause vastly more toxicity than AVA6207's (the EXd + PARPi version) slow leakage into the bloodstream - win 2

• given sequentially, the effect at the site of the tumour will, as with the first pass effect, be reduced - win 3

"Various topoisomerase 1 (TOP1) inhibitors have been combined with PARP inhibitors (PARPi) in preclinical studies and clinical trials, though significant dose-limiting toxicities, primarily myelosuppression, have historically limited their use.

"Combination with irinotecan: Clinical trials have explored combining PARP inhibitors like olaparib and veliparib with irinotecan.

• Clinical results: Early studies found that continuous dosing of PARPi with irinotecan was poorly tolerated due to severe toxicities like diarrhea and neutropenia.

• Mitigating toxicity: Intermittent dosing schedules were developed to improve tolerability, though dose reductions for both agents were still necessary."

What is the life expectancy criterion for patients enrolled on the trial?

I read the other day that when a topoisomerase 1 inhibitor and a PARP inhibitor are given together, they are complementary but their side effects are additive so the dosage of each has to be reduced. Sounds like swings and roundabouts. You don't get that same problem when the warheads are dumped inside the tumour.

@LLP, as well as Pfizer for exatecan+MMAE, there is indeed also Pfizer for exatecan+talazoparib (a PARP inhibitor)

Talazoparib (brand name Talzenna) is a highly potent poly-ADP ribose polymerase (PARP) inhibitor used to treat specific forms of breast and prostate cancer. It is considered powerful because of its "PARP-trapping" effect, which is about 100 times more potent than other PARP inhibitors and prevents cancer cells from repairing themselves.

Talazoparib is under patent until July/October 2029.

Correction (with missing bit from Combination of two distinct anti-cancer mechanisms...)

The pre|CISION ® dual payload pipeline currently comprises two approaches:

• Combination of two distinct anti-cancer mechanisms with clinical activity: Microtubule inhibition and Topo I inhibition (MMAE and exatecan)

• DNA damage response (DDR) agents ATR or PARP inhibitors with exatecan: Inhibition of DNA repair potentiates the effect of exatecan 2, 3

The pre|CISION ® dual payload pipeline currently comprises two approaches:

• Combination of two distinct anti-cancer mechanisms with clinical activity: Microtubule exatecan)1

• DNA damage response (DDR) agents ATR or PARP inhibitors with exatecan: Inhibition of DNA repair potentiates the effect of exatecan 2, 3

- - - - -

While dual payload ADCs are in development in oncology4 , Avacta is the first company to develop Dual Payload Peptide Drug Conjugates.

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pre|CISION® peptide drug conjugates (PDC) offer key advantages over conventional ADC approaches:

• Tunable, tumor-specific release that has been shown in the clinic to have two distinct advantages:

--- (1) Striking concentration of payload in the tumor vs plasma with a concentration of 100:1 (compared with ADC and other PDC that concentrate up to 10X)

--- (2) Dramatic reduction in off-target toxicities associated with the payload (AVA6000, pre|CISION® doxorubicin Phase 1 results 5-7 )

• Optimized bystander MoA that results in extracellular, rather than intracellular release of the payload, leveraging payloads with excellent membrane permeability 8

• Two clinical stage single payload programs:

--- (1) Faridoxorubicin (FAP-Dox, AVA6000) completed Phase 1 testing and currently enrolling expansion cohorts (NCT04969835)

--- (2) FAP-Exd (AVA6103) with the Phase 1 start scheduled Q1 2026

Https://avacta.com/pipeline/

Dual payload system: The dual payload pre|CISION platform was designed for the management of difficult to treat cancers by releasing more than one payload at the same time in the tumor microenvironment. The first molecules are designed with a potent topoisomerase I inhibitor and targeting the key resistance mechanism of DNA damage repair.

This is the abstract for today's poster:

"The proprietary pre|CISION® technology incorporates a peptidic substrate that is specifically cleaved by Fibroblast Activation Protein α (FAP). FAP is a post-proline protease that is overexpressed on the surface of cancer associated fibroblasts (CAFs) in many solid tumors, and facilitates delivery of pre|CISION® medicines specifically to the tumor microenvironment (TME). Previously we have presented AVA6103, a pre|CISION® -enabled exatecan candidate in IND-enabling studies. AVA6103 consists of exatecan, a potent Topoisomerase I inhibitor, covalently linked to a dipeptide containing a cleaving sequence (D-Ala-L-Pro), which is susceptible to hydrolysis by FAP but is resistant to hydrolysis by other mammalian proteases. Exatecan has been investigated both as a single agent and as a warhead in ADC therapeutics in the clinic. However, clinical utility of this family of warheads is limited by dose-limiting toxicities, including severe neutropenia. The exquisite selectivity of the pre|CISION® substrate for FAP results in release of exatecan warhead in the TME, greatly increasing the therapeutic window and hence reducing systemic exposure and associated toxicities. Drug combinations are commonly used in cancer therapy to improve outcomes and overcome resistance, therefore we hypothesized that incorporating two complimentary warheads into a single pre|CISION® molecule may offer similar benefits whilst minimizing systemic toxicity. To create dual warhead pre|CISION® PDCs, a series of compounds have been engineered with modifications in the capping-group and linker portions. Using structure-based drug design, clear structure-activity relationships have been established for affinity to, and susceptibility of linker cleavage by FAP and subsequent warhead release. We now demonstrate how the use of the precision technology platform has been widened to selectively control the release of multiple warheads from a single molecular species via a FAP cleavable linker. Selective release has been demonstrated through the use of kinetics showing the ability to tune the individual release of each warhead and in cellular studies showing potent cytotoxicity and bystander activity in cell-based assays including tumor cell-fibroblast 3D co-culture models. Induction of downstream pharmacodynamic markers for each warhead have also been evaluated. We show the potential of the technology to deliver a therapeutically relevant combination of warheads specifically to the TME while reducing systemic dose-limiting toxicities. This broadens the utility of the pre|CISION® platform in the delivery of novel medicines."

https://aacrjournals.org/mct/article/24/10_Supplement/C123/766596/Abstract-C123-Discovery-and-characterization-of