On September 16, 2026 Avacta Therapeutics (AIM: AVCT), a life sciences company developing innovative, targeted oncology drugs, reported that it has achieved clinical proof of mechanism for AVA6103, its next-generation controlled-release pre|CISION peptide-drug conjugate (PDC) platform in the ongoing phase 1 FOCUS-01 trial.
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Preliminary data from the Phase 1a trial of AVA6103 in patients with select solid tumors demonstrate proof of mechanism with two key findings:
AVA6103 pre|CISION controlled-release exatecan demonstrates a clean safety profile through the first three dose levels, including a payload dose level 50% higher than the maximum tolerated dose (MTD) of conventional exatecan, and
The comparison of the preclinical modeled pharmacokinetic (PK) data and clinical trial PK data demonstrates an exceptional alignment through the first 3 dose levels with controlled release of exatecan evident in patients for days after dosing
The alignment of these critical datasets greatly increases our confidence that the safety profile, tumor selectivity and antitumor efficacy observed in the preclinical studies of AVA6103 will translate into the clinic.
The first head-to-head comparison of AVA6103 and Enhertu, a marketed antibody drug conjugate (ADC) that targets HER2, demonstrates that AVA6103 shows better antitumor activity vs. Enhertu, with deep and durable responses delivered by our dose dense regimen that has been applied in the FOCUS-01 trial.
Christina Coughlin, CEO of Avacta, commented:
"We are thrilled to report the proof of mechanism data with our first Next-Generation pre|CISION molecule in the clinic, which continues to underscore the potential of our platform to make a significant difference to cancer patients. AVA6103 moved from candidate status to Investigational New Drug application in less than a year, and has now reached an initial clinical readout with excellent safety and PK data, showing it is performing exactly as expected from the data generated in our preclinical studies.
"Our head-to-head comparison with the marketed ADC Enhertu shows better activity in a HER2+ preclinical model even at low FAP levels, with the dose-dense regimen demonstrating advantages of AVA6103 over traditional dosing of ADCs.
"We continue our discussions with potential partners on the Next Gen assets and these data greatly increase our partnering position across the Next Gen platform. The FOCUS-01 trial continues to enroll patients into two parallel arms and we look forward to providing further updates as the trial progresses.
"With FAP expression in ~90% of solid tumors, these clinical findings provide a gateway for Avacta to link multiple payloads and access previously unaddressable markets. This is a major inflection point for our Next Gen pre|CISION platform, providing the opportunity for pipeline expansion to benefit patients and shareholders alike."
Clinical Proof of Mechanism of AVA6103 in the FOCUS-01 Trial
Trial design and progress:
The FOCUS-01 Phase 1 clinical trial of AVA6103 is enrolling patients with locally advanced or metastatic disease with one of six indications, being: colorectal cancer, pancreatic ductal adenocarcinoma, gastric/gastroesophageal junction cancers, cervical cancer or small cell lung cancer.
The first three dose levels have completed enrollment of patients (n=19) in two parallel arms with doses administered every two weeks (Q2W) or every three weeks (Q3W) and assessed for safety and tolerability, PK / pharmacodynamics (PD) and preliminary efficacy. The first three dose levels in the AVA6103 trial were 1.5 mg/m2, 3 mg/m2 and 4.5 mg/m2 to enable the comparison to both the Phase 1 trial of Enhertu and conventional exatecan:
The first three dose levels are similar to the absolute payload dose levels in the published Enhertu Phase 1 trial (Doi, et al. 2017);
Dose level 2 of AVA6103 is similar to the MTD of conventional exatecan (Rowinsky, et al. 2000); and
Dose level 3 represents an approximate 50% increase over this MTD of conventional exatecan.
Safety, tolerability and PK data in the first three dose levels are presented. Screening is ongoing for enrollment of patients into both the Q2W and Q3W arms at dose level 4.
Safety data
Patients in the FOCUS-01 trial were treated with escalating doses (1.5 mg/m2 to 4.5 mg/m2) and assessed for safety and tolerability. These data were compared with published data for Enhertu (releasing a highly similar payload, deruxtecan) and with conventional exatecan administered in the standard regimen (once daily for five days).
The safety profile of AVA6103-derived exatecan is highly favorable at the first three dose levels when compared with equivalent dosing of topoisomerase I inhibitors (Topo Ii) (conventional exatecan and Enhertu-derived deruxtecan), with minimal toxicity reported with AVA6103.
Notably, AVA6103 produced little toxicity at the equivalent and escalated doses of the MTD of conventional exatecan in heavily pretreated patients (Rowinsky et al. 2000) and at similar payload doses in the first three cohorts in the Phase 1 of Enhertu (Doi et al. 2017). Relevant comparison data include:
Neutropenia: 0% with AVA6103, 22% with similar doses of Enhertu, and 64% at the MTD of conventional exatecan (equivalent to the 3 mg/m2 dose of AVA6103).
Thrombocytopenia: 5% (1/19) with AVA6103, 11% with Enhertu and 43% with conventional exatecan;
Anemia: 16% (3/19) with AVA6103, 11% with similar doses of Enhertu and 43% with conventional exatecan; and
Nausea and vomiting: 5% (1/19) with AVA6103, 44% with Enhertu and 67% with exatecan (reported across all dose levels in this trial).
Pharmacokinetic data
Patients were assessed for plasma PK properties across the first three dose levels of AVA6103 and compared to the corresponding dose levels of Enhertu.
As seen previously in preclinical models, the first three dose levels in the trial demonstrate rapid reduction in the plasma level of the PDC (AVA6103), with prolonged low-level release of both products of the cleavage reaction, the pre|CISION peptide and released exatecan.
Given the very short half-life of the released peptide (2-3 hours) that was demonstrated in the AVA6000 program, and the detection of low levels of the released peptide from AVA6103 in the plasma up to 48 hours after dosing indicates that the PDC is being retained in the tumor in a ‘drug reservoir’ that is slowly being cleaved to release the peptide and exatecan, as this mechanism was designed to do.
The remarkable consistency of these results with predictive PK modeling based on preclinical studies greatly increase our confidence that AVA6103 is performing as intended, and that the robust preclinical data will translate to the clinic and support ongoing dose-escalation and efficacy evaluation in the Phase 1 trial.
Preclinical efficacy comparison with Enhertu
The comparative efficacy of Enhertu and AVA6103 was tested in a head-to-head format using a gastric cancer patient-derived xenograft model that is HER2+ and FAP+ (by IHC).
When tumors had grown to 100-200 mm3 in size, animals were randomized to receive either AVA6103 or Enhertu at the preclinical dose with evidence of activity (Enhertu x 1 or AVA6103 QWx3 dose dense regimen).
Enhertu treatment resulted in a slowed growth compared to vehicle control, with two animals demonstrating small tumor reductions and 1/6 with progression as best response. In comparison, AVA6103 treatment resulted in deep and prolonged partial responses in 6/6 animals treated.
Outlook
The design of the FOCUS-1 trial of AVA6013 and preclinical updates will be presented in Trials in Progress presentations at both the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Conference on Pancreatic Cancer, being held on September 25-28, 2026, and the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress, being held on October 23-27, 2026.
First efficacy data from the FOCUS-01 trial with AVA6103 is anticipated to be presented in H1 2027 – including data from clinical tumor biopsies which are anticipated to confirm AVA6103 is being retained in a ‘drug reservoir’ in the tumor, based on the preliminary Phase 1 data.
The selection of the payloads and data to support clinical candidate selection for the Dual Payload Next Gen Program (AVA6207) will be presented in Q4 2026.
Clinical data from the First Gen faridoxorubicin (AVA6000) program will also be presented in Q4 2026 at the ESMO (Free ESMO Whitepaper) Congress.
Enhertu (trastuzumab deruxtecan; T-DXd) is a protease cleavable-linker ADC, approved for both breast cancer and gastric cancer indications (an AstraZeneca/Daiichi Sankyo product). Enhertu is a registered trademark of Daiichi Sankyo Company, Limited and AstraZeneca.
(Press release, Avacta Life Sciences, SEP 16, 2026, View Source [SID1234670910])