Avacta Group Regulatory News (AVCT)

Avacta presents first preclinical data from dual payload pre|CISION® medicines at the 2025 AACR-NCI-EORTC International Conference on Molecular Targets

First-in-class dual payload peptide drug conjugate delivers two complementary therapies from a single molecule with potential to overcome resistance and maximize tumor control

LONDON and PHILADELPHIA - October 27, 2025 - Avacta Therapeutics (AIM: AVCT, 'Avacta', 'the Company'), a clinical stage biopharmaceutical company developing pre|CISION®, a tumor-activated oncology delivery platform, announces it presented preclinical data demonstrating its novel first-in-class dual payload pre|CISION® technology (AVA6207) at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics on October 25, 2025 in Boston, Massachusetts.

The data presented showcase the Company's innovative approach to delivering two distinct therapeutic payloads simultaneously to the tumor microenvironment (TME) through a single fibroblast activation protein (FAP)-mediated cleavage event. Avacta is the first company to develop dual payload peptide drug conjugates (PDCs), circumventing resistance mechanisms that cancer cells develop against single-drug therapies while maximizing therapeutic effect through targeted combination delivery. This approach has the potential to address several critical challenges in cancer therapy.

The Company's dual payload pipeline currently comprises two strategic approaches: combination of microtubule inhibition and topoisomerase I inhibition (MMAE and exatecan), representing two distinct anti-cancer mechanisms with established clinical activity; and DNA damage response (DDR) agents (ATR or PARP inhibitors) combined with exatecan, where inhibition of DNA repair potentiates the cytotoxic effect of exatecan.

Christina Coughlin, M.D., Ph.D., Chief Executive Officer of Avacta, commented:

"The first dual payload peptide drug conjugate marks an important step forward in oncology therapy, significantly extending the potential of our pre|CISION® platform by implementing combination cancer therapy in a single small molecule medicine. The synergistic enhancement in anti-tumor activity observed with our exatecan-DDR inhibitor combinations highlights the potential of targeting the tumor with a potent cytotoxic drug while attacking the known resistance mechanisms. We believe this technology has the potential to markedly improve outcomes for cancer patients, particularly those with highly-resistant tumors.

"The pre|CISION® platform has been validated by compelling clinical data with faridoxorubicin (AVA6000, FAP-Dox), demonstrating a tumor-to-plasma payload concentration of 100:1 and a significant reduction in off-target toxicities despite dosing up to approximately 4x the dose of conventional doxorubicin. The new dual payload intellectual property extends the platform to release two drugs from one pre|CISION® molecule, targeting highly-resistant cancers by addressing key resistance mechanisms."

Key Preclinical Findings:

The pre|CISION® dual payload technology demonstrated robust FAP-selective delivery and potent anti-tumor activity across multiple complementary payload combinations:

· Validated dual payload release mechanism: Biologic and biochemical analyses confirmed simultaneous release of two independent payloads from a single FAP cleavage event. Modifications to the self-immolative linkers enabled tunable payload delivery kinetics, providing flexibility to optimize therapeutic profiles for different payload combinations. Strategic modifications of linker and capping group structures enabled optimization of compound activity.

· FAP-selective tumor cell killing with maintained potency: Dual payload compounds achieved potent cytotoxic activity comparable to free payloads in the presence of FAP (IC50 values of 2-9 nM), while demonstrating minimal activity without FAP (IC50 >100 nM), confirming excellent tumor selectivity in 2D and 3D tumor spheroid models over the course of seven days.

· Confirmed dual mechanism biomarker modulation: Target-specific biomarkers for both payloads were modulated only in the presence of FAP. FAP-Exd/MMAE compounds induced decreased TOP1 levels, DNA damage markers (γH2AX, pCHK1), tubulin depolymerization, M-phase arrest, and characteristic S-phase and G2/M cell cycle arrest patterns, confirming both mechanisms of action were operational.

· Enhanced synergistic activity addressing resistance mechanisms: FAP-Exd/PARPi and FAP-Exd/ATRi compounds demonstrated 4-5 fold greater FAP-dependent tumor cell killing compared to exatecan alone, directly addressing the known DDR-mediated resistance pathway to topoisomerase I inhibitors. FAP-dependent biomarker modulation confirmed payload release (reduced TOP1, PAR, and pCHK1 levels) alongside elevated DNA damage and apoptosis markers (γH2AX, cleaved PARP), with synergistically increased γH2AX demonstrating enhanced therapeutic effect.

· Validated bystander mechanism in physiologically relevant 3D models: Tumor-fibroblast co-culture 3D spheroid studies confirmed that FAP-positive cancer-associated fibroblasts mediate payload release, resulting in concentration of both therapeutics in the TME and effective killing of FAP-negative tumor cells. Activity was dependent on FAP presence, with minimal effect in monocultures or upon FAP inhibition, validating the bystander mechanism of action.

Dual payload cancer therapies represent a highly novel approach in oncology with the first dual payload antibody drug conjugates (ADCs) emerging in recent years. The pre|CISION® platform has four key advantages over traditional ADC delivery, including tumor-specific payload release that avoids the toxicities associated with nonspecific release, small molecule manufacturing, better tumor penetration and bystander effect, along with a large addressable market of 90% of solid tumors.

The poster presentation (Abstract #C123) titled "Discovery and characterization of novel pre|CISION® technology compounds delivering complementary dual payloads to the tumor microenvironment following FAP cleavage" is available on the Company's website at www.avacta.com.

The Avacta team will deliver a presentation via Investor Meet Company to review the published data upon their return from the Congress at 16:00 GMT on Wednesday October 29, 2025. Details for the webinar will be posted on the Avacta home page and available through the Investor Meet Company platform.

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About pre|CISION®

The key aspect of pre|CISION® is its peptide drug conjugates (PDC) technology. The combination of the cancer drug and the proprietary cleavable peptide (the PDC) is inert and incapable of entering cells and killing them until the peptide is specifically released within the tumor. The active payload in the pre|CISION® PDC is released when the PDC comes into contact with the common tumor-associated protein, known as fibroblast activation protein (FAP), in the tumor. The release of the payload from the pre|CISION® product directly in the tumor results in higher concentration of the drug at the tumor and lower blood and healthy tissue levels than standard systemic administration, offering the potential to improve efficacy and patient tolerability.

About Avacta - www.avacta.com

Avacta is a clinical stage life sciences company developing an innovative proprietary drug delivery peptide drug conjugate (PDC) platform, pre|CISION®. The pre|CISION® platform uniquely enables the repurposing of a range of oncology drugs as PDC payloads with the goal to significantly reduce toxicity and side effects for patients by concentrating the drug directly in the tumor.