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To Gemini: How did the in vivo AVA6000 work with mice translate to data in humans?

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Preclinical in vivo studies of AVA6000 in mice successfully translated to human Phase 1 clinical trials by demonstrating that the pre|CISION™ platform selectively releases the chemotherapy agent doxorubicin within the tumor microenvironment (TME), leading to reduced systemic toxicity and encouraging antitumor activity. Key findings from mice—such as high FAP-mediated cleavage, minimal systemic toxicity, and strong efficacy in FAP-positive tumor models—were mirrored in human patients, showing improved safety and efficacy compared to traditional doxorubicin.

[Continues with details]

Whatever your prompt was, the AI response lacks context as it does not take into account all that has gone on before with AVA6000, and even AVA3996.

The usual generic guff about 'The "Preclinical" Gap' and 'Safety Uncertainty', as reproduced below, are where context is missing as cleavable dipeptide link PLUS known oncolytic PLUS trial continuing EQUALS this works as expected.

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The "Preclinical" Gap: Almost all the "robust activity" and "favorable kinetics" mentioned are based on animal/PDX models. Success in mice frequently fails to translate to the same efficacy or safety in humans.

Safety Uncertainty: While the goal is "minimizing systemic toxicity," the actual safety profile in humans will not be known until the Phase 1 data is released (expected late H2 2026).

...Or just those two indications have been added to Phase 1a.

All will no doubt become clear in due course – updated ClinicalTrials record, CC explainer, or Science Day.

From today's RNS:

"Based on favorable preclinical activity and biomarker readouts from the strategic collaboration with Tempus, two indications have been added to the trial: colorectal cancer (CRC) and hormone receptor-positive breast cancer (HR+ BC)"

The Pipeline page https://avacta.com/pipeline/which was updated fairly recently and currently says :

"Expansion cohorts are planned in additional FAP+ cancers including hormone-receptor positive breast cancer (HR-BC), non-small cell lung cancer (NSCLC) and colorectal cancer (CRC)."

So I guess they have either subsequently added another Phase 1b indication to what was in today's RNS (which talks about what is related to the poster prepared some time ago) or they have removed non-small cell lung cancer (NSCLC).

RNS's on the London Stock Exchange site include hyperlinks – a link to the FOCUS-01 study, NCT07454642, in this case. RNS's on LSE do not.

This analysis ignores pre|CISION history.

"AVA6103 the Preclinical Poster No 5846 regarding Exatecan will be highlighted by Prof Banerji tomorrow in San Diego along with the Dual Payload Poster No 5656"

Prof Banerji will be presenting the ICR poster, "7173: Mechanistic studies of fibroblast activation protein activated prodrug AVA6000 in pancreatic and liposarcoma models", on Wednesday.

The presenters for the two Avacta posters tomorrow are:

AVA6103: Curtis Rink (Preclinical Program Lead) - "5846: AVA6103 is a FAP-enabled pre|CISION®peptide-drug conjugate delivering sustained release of exatecan in the tumor microenvironment with potent antitumor activity"

AVA6207: Victoria Juskaite (*) - "5656: Characterization and translational development of novel pre|CISION® technology compounds delivering complementary dual payloads to the tumor microenvironment following FAP cleavage"

* I'm guessing that Victoria Juskaite is the program lead for AVA6207 as she is the first-named presenter/author and I think it is the convention to have the main person listed first. She is also the name in the Author field for the 'Avacta meets Novartis: Pre|CISION single and dual warheads' slide deck that has been used and updated and reused and modified and reused, etc. recently.

To plan an additional three Phase 1b cohorts they will need to have been fairly confident of having the funding one way or another, either cash inhouse to do it or a partner to fund one or more of the cohorts for these new indications. Alternatively, maybe they are just wanting to cover most of the main likely successful indications during this trial's Phase 1b whilst it's running rather than having to set up and do another Phase 1b in the future. In any case, their expansionist ambitions are good news.

Interesting!

The bar is low for faridox as well: https://aacrjournals.org/cancerres/article/86/7_Supplement/7173/780950

"The GI50 of AVA6000 in two pancreatic cancer cell lines ASPC-1 and Mia-Paca-2 in the co-culture system with PSCs was 58±21.4nM, (Stdev,n=3) and 66.5±16.3nM (Stdev, n=3)."

The GI50 for elraglusib (9-ING-41) is an order of magnitude higher than for AVA6000 (10^-7M vs 10^-8M) albeit for bladder cancer cell lines rather than pancreatic cell lines: https://pmc.ncbi.nlm.nih.gov/articles/PMC6934761/

"We tested 9-ING-41 in T24, HT1376 and RT4 bladder cancer cell lines. 9-ING-41 treatment resulted in a decreased growth of bladder cancer cells at 0.25–1 μM concentrations in a dose-dependent manner with GI50 range of 0.4–0.5 μM (Fig. 1A)."

GI50 (Growth Inhibition 50%) is the concentration of a compound, such as a drug, required to inhibit the growth of cells by 50% in in vitro studies. It is a critical metric in cancer research and pharmacology used to evaluate the potency of compounds that stop tumor cell proliferation, often used for cytostatic agents. The lower the concentration, the higher the potency.

I won't believe it's on until I see the backpacks.

If anyone hasn't twigged yet, the only thing wyndbum ABSOLUTELY LOVES is being the centre of attention.

Just use the filter or ignore or report falsehoods. Responding serves no purpose other than to encourage more tedious essays.

Narcissistic attributes often include a grandiose sense of self-importance, an excessive need for admiration, a lack of empathy, and a strong sense of entitlement. These traits—which can span from extreme self-centeredness to manipulative behavior—are often driven by an underlying, fragile self-esteem.

Yeah that's all well and good but it's still a fact that Avacta could be taken over for 10 times their present value with spare change from the back pocket of big pharma.

£3.5bn is small change for big farmer.

Ongoing | Cancer Accelerated Approvals: https://www.fda.gov/drugs/resources-information-approved-drugs/ongoing-cancer-accelerated-approvals

Verified Clinical Benefit | Cancer Accelerated Approvals: https://www.fda.gov/drugs/resources-information-approved-drugs/verified-clinical-benefit-cancer-accelerated-approvals

Withdrawn | Cancer Accelerated Approvals: https://www.fda.gov/drugs/resources-information-approved-drugs/withdrawn-cancer-accelerated-approvals

Grants at the National Institutes of Health? Slashed. FDA approvals expected based on past conversations with the agency? Denied. Tariffs? Sure, why not.

Every company in the business, whether small, large or in-between, has had to think hard about how to respond to this swirling turmoil. For most of the Big Pharmas that made our list of the top 10 R&D budgets of 2025, that meant taking a hard look at the very spending that earned them their spot.

All of this year’s top R&D spenders also appeared on last year’s list, and without spoiling the order, the majority of them made substantial cuts to their research budgets in 2025. Bristol Myers Squibb, Johnson & Johnson, Pfizer, Merck, AbbVie and Roche all cut their R&D spending last year compared to 2024, some by as much as 29%. Others did boost spending, but by marginal amounts that pale in comparison to their R&D increases in prior years.

[Continues, with details of the top 10]

https://www.fiercebiotech.com/special-reports/top-10-pharma-rd-budgets-2025

Discussion about the above: https://omny.fm/shows/the-top-line/the-top-10-pharma-r-d-budgets-of-2025

The number of drugs in development has fallen for the first time since the mid-1990s, according to a Citeline report. While methodological changes may have affected the result, the dip highlights a period when drugmakers trimmed their pipelines and cut the number of new projects starting development.

Citeline, which has tracked global drug development since the 1980s, has witnessed decades of growth in the number of drugs in development. The figures cover everything from new molecules in preclinical testing to approved products being evaluated in additional indications. From 2001 to 2025, the number of drugs in development increased every year, rising from 5,995 to 23,875.

Then the trend reversed. Citeline calculated that 22,940 drugs were in development at the start of 2026, down 3.9% on that time last year. The dip partly reflects a change in the company’s data collection systems, which it said likely artificially inflated the 2025 figure.

Yet that explanation only shifts the timing of the slowdown in the pipeline expansion. Accounting for the potentially anomalous 2025, Citeline said the number of drugs in development has “probably been fairly flat over the past few years.” If that assessment is accurate, the industry’s overall pipeline has plateaued at just under 23,000 molecules since 2024.

he number of drugs entering the pipeline fell 1.3% last year. Oncology remained the most active area of new drug development, accounting for 38.6% of programs joining the pipeline. Neurological disease is an increasingly active area. Having accounted for 12.7% of new candidates in 2023, neurological disease contributed 13.8% in 2024 and 14.4% in 2025.

Roche had the most drugs in development, 262, largely because former pace-setter Pfizer axed assets, according to the report. Pfizer fell to No. 3 in the rankings after cutting its R&D pipeline from 271 to 257 molecules. AstraZeneca leapfrogged Pfizer and Novartis, adding 20 candidates to its pipeline to climb to No. 2.

Novartis fell to No. 5 after trimming 10 programs, overtaken by Sanofi’s expanding pipeline.

Large drugmakers typically disclose programs only after they enter the clinic, meaning the data offer an incomplete snapshot of how pipelines are changing.

Across the 25 companies with the largest pipelines, the total number of assets in development increased by 32. However, that figure is inflated by the addition of 30 programs to BioNTech’s pipeline. Among the top 15 companies, the number of active assets fell by 10.

https://www.fiercebiotech.com/biotech/biopharma-rd-pipeline-shrinks-1st-time-30-years-report

Citeline report: https://www.citeline.com/en/rd26

In other instances, treatment with oncology products with initially positive signals on PFS has led to reductions in OS. This occurs most often when the magnitude of effect in tumor response or PFS is relatively small or treatment entails significant toxicity.93 The latter is often related to the long-standing industry practice of using maximum tolerated dose (MTD) in oncology trials. Dosing to MTD became an established norm in oncology during the development of cytotoxic chemotherapies, in which efficacy was inevitably linked with its adverse effects. The targeted therapies under development today break with that paradigm. Higher doses do not necessarily increase efficacy but do increase toxicity, which limits adherence to oral treatments delivered over longer timeframes, undermining clinical outcomes.93,94 For example, sotorasib (Lumakras®, Amgen), which received AA in 2021 for NSCLC, later became the subject of FDA concern regarding high-dose toxicity, leading the agency to request investigation of lower-dose alternatives. While survival on the higher dose was nominally longer than on the lower dose, side effects were also significantly more severe. Amgen nevertheless pushed ahead with developing the higher-dose version.95

Despite their frequent use, the correlation between surrogate endpoints such as PFS, objective response rate (ORR) and event-free survival (EFS) and OS varies widely, both within and across cancers and treatment types.96 While AA is designed to accept some degree of uncertainty, this raises questions about when and how to validate surrogate endpoints in oncology (and to varying degrees the other therapeutic areas of interest in AA as well). The FDA accepts validated surrogate endpoints, such as cholesterol lowering as a surrogate for cardiac events, in due course of regular approval, without the need for additional confirmatory trials. Although not rising to the level of validation, PFS and other intermediate endpoints may be more reliable predictors of OS in some types of cancers than others. Better understanding of these differences, which could be developed through meta-analyses of trials and/or observational studies, could allow FDA to manage AA more adaptively for cancer indications.

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Page 17 of the ICER report

Oncology

Surrogate endpoints used in AA for oncology are considered more well-established [than non-oncology]. It is possible that the FDA’s Oncology Center of Excellence (OCE) Project Confirm, which launched in 2021 and provides guidance and monitoring of AA in oncology, contributes to this view.88 Several oncology drugs approved through AA in recent years have dramatically improved patient outcomes. For example, Keytruda, which received AA for advanced melanoma in 2014 and full approval in 2015, significantly improved 10-year survival of the disease as compared with previously available treatment options.89 Similarly, improvements in lung cancer mortality have been tied to the rapid uptake of targeted therapies and checkpoint inhibitors for non-small cell lung cancer (NSCLC), many of which were first approved under AA.90

Yet AA for oncology is freighted with its own uncertainties, and studies continue to raise questions about whether patients ultimately experience clinically meaningful benefits, even with drugs that are ultimately converted to traditional approval. One third of oncology drugs that were approved under AA on progression-free survival (PFS) between 2013-2017 and subsequently converted to regular approval failed to demonstrate improvements in overall survival (OS) or quality of life (QOL).91 The rationaale for approving such drugs even when they fail in clinical trials is often related to clinical trial design.92 In some cases, patients enrolled in trials for molecularly-targeted drugs did not benefit from the drug’s mechanism of action.92 Lack of statistical power and certain trial designs may also contribute to less dramatic improvements in OS than PFS. For example, trials that allow rescue medication and crossover between treatment arms may underestimate survival benefits, as patients in the control arm often receive the experimental therapy upon progression, which can dilute observed OS differences. Finally, difficulties in trial recruitment for later-line use within an indication may force the deployment of confirmatory trials in earlier-line, less severe disease, which may make demonstration of substantial OS improvement more difficult.

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The FDA should strengthen the evidence required for drug approvals under its accelerated pathway and increase transparency surrounding those regulatory decisions, according to a report (PDF) from a prominent industry and government watchdog.

In the report, the Institute for Clinical and Economic Review (ICER) also recommends that advisory committees review drugs that are up for accelerated approval and that the pathway spell out more clearly the benefits and risks associated with the use of drugs approved under its purview.

“The goal of the accelerated approval pathway has always been to ensure that patients receive innovative treatments faster,” Sarah Emond, the CEO of ICER, said in a release. “We can point to several successes where patients have benefited from expedited access to transformative medications. However, there are also many instances of regulatory inconsistency, lagged development of confirmatory trial data and access restrictions that have limited patient use.”

https://www.fiercepharma.com/pharma/fda-should-increase-transparency-and-bolster-evidence-needed-accelerated-drug-approvals-icer

ICER report: https://icer.org/wp-content/uploads/2026/04/Strengthening-the-FDAs-Accelerated-Approval-Pathway-_-ICER-White-Paper-_-April-2026.pdf

ICER evaluates the cost-effectiveness of drugs in a similar way to the UK's NICE.

ICER: https://en.wikipedia.org/wiki/Institute_for_Clinical_and_Economic_Review

I disagree with your conclusions B2H, basically because I do not know the host's style and usual questions in such circumstances. I feel you are placing wishful thinking into your interpretation. Time will tell what and when any of the FDA goodies come Avacta's way. Until such time, all is speculation.