LONDON – Oct. 24, 2024 – Avacta Therapeutics (AIM: AVCT), a life sciences company developing next generation peptide drug conjugates (PDC) targeting powerful anti-tumor payloads directly to the tumor, today announces scientific presentations of two novel programs in its pipeline at the 2024 EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain. The presentations include data from two preclinical oncology assets, AVA6103 and AVA7100, from Avacta’s pipeline of pre|CISION® product candidates.
Both presentations take place today in the Antibody Drug Conjugate (ADC) poster session at the Symposium.
Avacta’s pre|CISION® product candidates are designed to be activated specifically in the tumor microenvironment (TME), thereby enabling improved antitumor activity while reducing systemic toxicities. Each peptide drug conjugate (PDC) in the Company’s pipeline is comprised of an active antitumor drug (known as a payload) linked to the pre|CISION peptide, which renders the payload inert and is cleaved only within the tumor by the action of Fibroblast Activation Protein, or FAP, expressed in the cancer associated fibroblasts in the TME. The pre|CISION® technology addresses key limitations of ADCs, namely (1) non-specific payload release that results in significant off target toxicities, and (2) the complexity of the bystander effect, which is necessary to target antigen-negative tumor cells and thus to treat antigen-low populations. The pre|CISION platform addresses these limitations by releasing payload only in the tumor microenvironment and optimizing the bystander mechanism of action.
AVA6103 is a pre|CISION-enabled PDC comprised of the pre|CISION peptide linked to exatecan, the most potent topoisomerase I (topo I) inhibitor in clinical development. AVA7100 is a part of a new class of pre|CISION®-enabled Affimer® drug conjugates with potential applications in multiple cancer types, including those with lower levels of FAP in the tumor. AVA6103 and AVA7100 are expected to enter IND-enabling studies in late 2024 and 2H 2025, respectively.
The details of these advances in the pre|CISION® technology are presented below.
Christina Coughlin, MD PhD, CEO of Avacta, commented:
“We are encouraged by the preclinical data from AVA6103 demonstrating that FAP-enabled exatecan induces DNA damage and drives cancer cell death and we look forward to advancing this promising therapy toward the clinic. The preliminary data from AVA7100 demonstrating that exposure to Affimer® Drug Conjugates (AffDCs) results in drug cleavage, release of the payload and tumor cell kill as a bystander function are exciting for this entirely new class of therapies.
“These presentations showcase the evolution of our pre|CISION® platform technology to selectively deliver highly potent payloads directly to the TME, while minimizing exposure in normal tissues and optimizing patients’ outcomes. Our first program, AVA6000, demonstrates a four- to six-fold increase in the therapeutic index in the clinic and in preclinical models. With the advances in the platform, we are now seeing a 75-fold increase in therapeutic index with our recently announced exatecan program, AVA6103 in preclinical models, suggesting that AVA6103 could have an unprecedented safety profile in the clinic. Potent topoisomerase I inhibitors are the payloads of ADC therapies in the clinic, although the non-specific release of these payloads can lead to severe off-target toxicities. Given the lack of these toxicities in our first program and the broad reach of the topoisomerase I inhibitor class, we see our next programs as having great potential for true impact in patients with high unmet need.”
AVA6103 Results
In a poster titled “The novel peptide drug conjugate AVA6103 is a FAP-enabled pre|CISION® medicine which targets Topoisomerase I to the tumor microenvironment via FAP cleavage” in vivo data were presented that demonstrate the ability to target and accumulate the active warhead in the tumor microenvironment, resulting in tumor growth inhibition with AVA6103.
Specifically, the key findings from the poster demonstrate:
- The therapeutic index of exatecan is significantly increased by pre|CISION enabling, specifically the maximum tolerated dose of pre|CISION exatecan (AVA6103) observed is 75 times that of conventional exatecan in a daily dosing regimen
- AVA6103 optimizes the bystander effect where the conjugate is only cleaved by FAP-positive fibroblasts, and released exatecan can enter FAP-negative cancer cells
- High intratumoral warhead concentrations are seen at 4hr and 24hr timepoints for several pre|CISION exatecan compounds, with up to 50-fold higher warhead concentrations in the tumor versus plasma in a patient-derived xenograft model,
- AVA6103 inhibits tumor growth, with complete responses noted in a preclinical treated model engineered with human FAP expression (HEK-FAP) tumors. Increased survival was also shown in this model treated with AVA6103 compared with other models with vehicle-treated tumors.
AVA7100 Results
A poster titled “Affimer® Drug Conjugates (AffDC) targeting Fibroblast Activation Protein-α deliver highly toxic warheads to the tumor microenvironment by leveraging the pre|CISION® release mechanism” include data demonstrating that exposure of tumor cell line or fibroblast cell co-cultures to AffDCs results in drug cleavage, release of the warhead and tumor cell kill as a bystander function.
Specifically, the key findings from the poster demonstrate:
- With non-internalizing Affimer protein binding and extracellular warhead release by FAP, the AffDC optimizes the bystander effect, leading to effective killing of antigen-positive and antigen-negative tumor cells
- AffDCs have an antigen-binding region of 14kDa (single-domain) or 28 kDa (two-domain) that is 10-20% of the size of an antibody, optimizing tumor penetration. AffDCs may be rapidly engineered for optimal biophysical and functional characteristics.
- The FAP AffDC molecules exhibit a broad range of FAP binding (including potency up to single-digit picomolar, pM) combined with highly tumor-specific warhead release by leveraging the preCISION linker to release warhead directly in the tumor microenvironment and target that delivery to tumors with low FAP expression.