Avacta Group plc presented updated Phase 1a trial data for AVA6000 at the 2024 European Society for Medical Oncology (ESMO) Congress, showcasing promising efficacy and a favorable safety profile in patients with Fibroblast Activation Protein (FAP)-positive solid tumors. The results indicate that AVA6000, a peptide drug conjugate (PDC) of doxorubicin, is well-tolerated and demonstrates durable responses, suggesting a potential advancement in targeted cancer therapy.
Clinical Efficacy and Safety
The Phase 1a trial, involving 57 patients, evaluated AVA6000's safety and efficacy with both every three weeks (Q3W) and every two weeks (Q2W) dosing schedules. Efficacy data from 49 patients showed notable responses in FAPhigh cancers, including soft tissue sarcoma and salivary gland cancer. Specifically, three partial responses and four minor responses were observed in this group.
Professor Chris Twelves, Lead Investigator and Professor of Medicine at the University of Leeds, commented, “The AVA6000 data presented at ESMO continue to demonstrate encouraging efficacy with several ongoing, durable responses. The observed efficacy aligns with a highly favorable safety profile including a lack of the significant cardiac toxicity that is often seen with doxorubicin treatment.”
Compared to conventional doxorubicin, AVA6000 exhibited a significantly improved safety profile. Severe neutropenia was observed in only 14% of AVA6000 patients, compared to 49% in those treated with conventional doxorubicin. Furthermore, there were no cases of febrile neutropenia in the AVA6000 trial, while 16.5% of patients receiving conventional doxorubicin experienced it. The incidence of left ventricular ejection fraction (LVEF) dysfunction was also lower with AVA6000 (12.3%) compared to conventional doxorubicin (48.4%).
Mechanism of Action and Pharmacokinetics
AVA6000 leverages Avacta’s pre|CISION™ technology, which is designed to target the tumor microenvironment (TME) by utilizing the FAP enzyme. The PDC consists of doxorubicin conjugated with a peptide moiety that is specifically cleaved by FAP, releasing the active warhead in the TME. This targeted release aims to reduce damage to healthy tissues and systemic side effects.
Pharmacokinetic data revealed that AVA6000 extends the plasma half-life of doxorubicin by approximately 40% and reduces its Cmax and peripheral volume of distribution by 40-50%. This suggests that AVA6000-released doxorubicin has a more limited distribution into normal tissues compared to conventional doxorubicin.
Christina Coughlin MD, PhD, Chief Executive Officer of Avacta, stated, “We believe our platform has the potential to revolutionize cancer treatment by enabling patients to achieve improved outcomes with fewer side effects by leveraging the tumor specific enzyme FAP to protect normal tissues from toxic drugs.”
Implications for Future Development
The trial results indicate that AVA6000 is well-tolerated across both Q2W and Q3W dosing schedules, with no maximum tolerated dose identified in either arm. The data also suggest that lower levels of FAP activity are sufficient for warhead release, expanding the potential target population to include FAPmid tumor types.
These findings support the continued development of AVA6000 and the pre|CISION™ platform, with the aim of improving cancer treatment outcomes by enhancing efficacy and reducing toxicity.
