Avacta Group Plc announced the presentation of interim results from the Phase 1 clinical trial of peptide drug conjugate AVA6000 at the American Association for Cancer Research (?AACR?) annual meeting in San Diego, USA. The results to date show that AVA6000, the first peptide drug conjugate in the Avacta pipeline, has a favorable safety profile with concentration of the warhead in the TME resulting in multiple responses in patients with high levels of Fibroblast Activation Protein (?FAPhigh?), thus delivering clinical proof-of-concept for AVA6000 and proof-of-mechanism for the proprietary pre|CISIONTMdrug delivery platform. Many solid tumors have higher levels of FAP compared with healthy tissues.

Avacta's pre|CISIONTM technology is designed to leverage the tumor-specificity of FAP expression by rendering a therapeutic warhead inert with the bound peptide moiety attached to the warhead, until it encounters FAP and is cleaved, releasing active warhead into the TME. FAP targeted release of the warhead specifically in the TME aims to reduce damage to healthy tissues and systemic side effects, improving the tolerability for patients and allowing optimization of the dosing schedule to improve efficacy. Data demonstrate clinical proof of concept for AVA6000 with multiple patient responses: Seven dose cohorts (n=42) were completed in the Phase 1a Arm 1 of the trial with a dosing schedule of every three weeks (?

Third Quarter W?) at the time of the data cut-off on March 11, 2024. All 42 patients enrolled were evaluable for safety (primary outcome measure) and for efficacy (secondary outcome measure). At the time of the data cut-off, enrollment continues in the every two weeks (?

Second Quarter W?) Phase 1 Arm 2 dose cohort. For analysis of the efficacy, cancer indications were categorized as FAPhigh (soft tissue sarcoma and salivary gland cancer) or FAPmid (pancreatic cancer, colorectal cancer, lung cancer and other malignancies). Patients with indications considered FAPlow were excluded from the trial.

Among patients with FAPhigh cancers (n=15), 2 partial responses and 3 minor responses were observed, including:? A durable confirmed partial response in a 60-year-old male patient with the diagnosis of undifferentiated pleomorphic sarcoma with duration of response of 34 weeks. This patient had progressed on prior therapy and imaging studies demonstrate near complete resolution of pleural metastases with a reduction of 74% in the sum of longest diameters per RECIST version 1.1; An unconfirmed partial response in a 79-year-old male patient with salivary gland cancer with deepening of response to a 57% decrease in the sum of diameters; Two patients with dedifferentiated liposarcoma with minor responses of >12% reduction in the sum of diameters; and All four responders above remain on study at the time of the data cutoff.

Meaningful stable disease of longer than 16 weeks and/or response was observed in 10 patients resulting in a disease control rate of 10/15 (67%). No responses were observed among patients with FAPmid indications (n=27) and stable disease >16 weeks was observed in 10 patients for a disease control rate of 10/27 (37%). Treatment with AVA6000 was well tolerated and a reduction in AVA6000-related treatment-emergent toxicities as compared with standard dose doxorubicin was noted with respect to both severe and mild to moderate toxicities.

Regarding severe toxicities (grade 3-4), a steep reduction in neutropenia was observed when compared to standard dose doxorubicin (with AVA6000, 16.7% of patients reported severe neutropenia versus 49% with standard dose doxorubicin). There were no cases of febrile neutropenia in the AVA6000 trial compared to 16.5% of patients receiving doxorubicin alone. Reductions were observed as well in toxicities that impact quality of life (any grade), including nausea (reported by 33.3% of patients with AVA6000 versus 67% with doxorubicin) and mouth sores (mucositis, 7.1% with AVA6000 versus 41% with doxorubicin).

Other toxicities with reductions include musculoskeletal pain, loss of appetite and constipation. Two dose limiting toxicities were observed (cardiac failure and neutropenia/thrombocytopenia), but in both cases the dose cohorts were expanded and deemed safe. Thus, the safety profile of AVA6000 administered on a once every three weeks basis was favorable compared to standard dose doxorubicin and the first arm of the Phase 1 did not identify a maximum tolerated dose.

Pharmacokinetic and pharmacodynamic modelling in the trial demonstrate that AVA6000 delivers a high concentration of doxorubicin to the tumor microenvironment relative to plasma, as designed in the pre|CISION platform. This concentration of the warhead in the TME results in antitumor activity in tumors with reported high expression of FAP. In addition, exposure-response modelling and comparison with serum FAP suggests the derived, free doxorubicin is generated by tumor cleavage of AVA6000 versus peripheral blood cleavage.

Based on this very favorable three-weekly dosing safety profile, Avacta continues to enroll patients in the two-weekly dosing safety study. The combined data from the three-weekly and two-weekly studies will provide information to allow Avacta to define the dose and schedule to be used in efficacy studies. Patients can be dosed in parallel in the two-weekly dose escalation study and Avacta remains on track to begin the dose expansion efficacy study in the second half of 2024 in the US.

The data from the expansion study will be used to inform the optimal choice of a single indication for the Phase 2 efficacy study which will follow the expansions, subject to FDA approval.