Avacta reports clinical proof of mechanism for AVA6103 PDC in FOCUS-01
Avacta Therapeutics has announced clinical proof of mechanism for AVA6103, its next-generation FAP-activated peptide-drug conjugate (PDC), from the ongoing Phase 1 FOCUS-01 trial. The AIM-listed oncology company said preliminary data from the first three dose cohorts confirm the controlled-release mechanism is working as intended, with pharmacokinetic (PK) behaviour in patients closely matching preclinical predictions.
The FOCUS-01 trial is enrolling patients with locally advanced or metastatic disease across six solid tumour types: colorectal cancer, pancreatic ductal adenocarcinoma, gastric and gastro-oesophageal junction cancers, cervical cancer, and small cell lung cancer. Nineteen patients have completed the first three dose levels, administered at 1.5, 3.0, and 4.5 mg/m2 in two parallel arms dosed every two or three weeks.
Safety and pharmacokinetics
The safety comparison with published data is noteworthy. At dose level three, which represents approximately 50% above the maximum tolerated dose of conventional exatecan, AVA6103 produced no neutropenia in patients versus 22% at comparable payload doses in the Enhertu Phase 1 trial and 64% at the equivalent exatecan dose. Rates of nausea and vomiting were also substantially lower: 5% with AVA6103 compared with 44% for Enhertu and 67% for conventional exatecan.
Avacta attributes the improved tolerability to the PDC's tumour-localised release mechanism. The pre|CISION platform uses fibroblast activation protein (FAP), a protease expressed in the tumour microenvironment, to cleave the conjugate and release exatecan preferentially at the tumour site. Detection of released peptide in plasma up to 48 hours after dosing suggests the PDC is accumulating in a drug reservoir within the tumour before slow cleavage, consistent with the intended mechanism.
Chief executive Christina Coughlin said the PK and safety data were "performing exactly as expected" from preclinical work and that a head-to-head preclinical comparison with the AstraZeneca and Daiichi Sankyo antibody-drug conjugate Enhertu showed AVA6103 delivered deep and durable partial responses in all six animals treated in a HER2-positive gastric cancer xenograft model, versus a more limited response profile for Enhertu at its active preclinical dose.
Market context and competitive landscape
The comparison with Enhertu is commercially pointed. Enhertu has become a significant commercial benchmark in the ADC space since approvals in breast and gastric cancer, and Avacta is directly positioning AVA6103 as a candidate capable of offering superior tolerability and, in preclinical settings, superior antitumour activity. Whether that translates to the clinic will be the central question when first efficacy data from FOCUS-01 are presented, which the company anticipates will occur in the first half of 2027.
The broader PDC and XDC space is drawing increasing attention from larger biopharma as the ADC market matures. FAP as a tumour-targeting mechanism is being explored by several academic groups and biotechs given its expression profile across roughly 90% of solid tumours, creating a potentially large addressable population. Avacta's approach using a small-molecule format rather than a bulky antibody carrier is one of several delivery innovations competing for the next wave of XDC partnerships.
Avacta said it is in active discussions with potential partners for the Next Gen platform and expects to present data on payload selection for its dual-payload programme AVA6207 in the fourth quarter of 2026. Trial-in-progress presentations for FOCUS-01 are scheduled at the AACR Pancreatic Cancer conference in late September and at ESMO in October. Enrolment is continuing into dose level four across both dosing schedules.