Avacta reported preliminary Phase Ia data for AVA6103, a fibroblast activation protein (FAP)-activated peptide-drug conjugate delivering the topoisomerase I inhibitor exatecan, showing early clinical evidence that the molecule is behaving in patients broadly as predicted by preclinical models. In the FOCUS-01 trial, 19 heavily pretreated patients have received AVA6103 across the first three dose levels, up to 4.5 mg/m². No neutropenia was observed, while thrombocytopenia and nausea or vomiting were each reported in one patient.
Pharmacokinetic data provided the main evidence supporting the proposed mechanism. Intact AVA6103 declined rapidly in plasma after dosing, while low levels of cleaved pre|CISION peptide and free exatecan remained detectable for up to 48 hours, which Avacta said is consistent with sustained cleavage of drug retained in tumor tissue. Dose escalation is continuing, with initial efficacy and tumor-biopsy data expected in H1 2027.
AVA6103 is designed to exploit FAP, a protease highly expressed in the tumor microenvironment, to release exatecan preferentially within tumors rather than systemically. The approach differs from antibody-drug conjugates such as Enhertu and Datroway, which use tumor-associated cell-surface antigens to deliver topoisomerase I inhibitor payloads. Avacta is seeking to use FAP-triggered cleavage and sustained intratumoral release to widen the therapeutic window of exatecan, a potent topoisomerase I inhibitor whose conventional development was limited by systemic toxicity. AVA6103 is the second clinical program from Avacta’s pre|CISION platform (and the first using its sustained-release design), following AVA6000 (FAP-Dox), a FAP-activated form of doxorubicin.
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