Building a pipeline of clinically-differentiated cancer therapies

As previously reported by DDW, Avacta Group has dosed the first patient in its Phase I multicentre trial evaluating AVA6000, a novel pro-drug of Doxorubicin and the company’s first therapeutic based on its pre|CISION technology. Megan Thomas speaks Dr Alastair Smith, Chief Executive Officer of Avacta Group, about this development. MT: You previously commented that this study marks the transformation of Avacta Life Sciences into a clinical stage biopharmaceutical company. Can you elaborate on this and what it means for the company and the drug discovery sector? Avacta is entering an exciting stage in its mission to build a pipeline of clinically-differentiated cancer therapies. AVA6000 is Avacta’s first therapeutic based on the pre|CISION platform to reach the clinic. It is a tumour-activated form of the chemotherapy Doxorubicin, a standard of care for the treatment of several cancers with a market expected to grow to $1.38 billion by 2024. However, chemotherapies, including Doxorubicin, often have very severe systemic side effects that limit their use, and therefore ultimately limit the benefit to patients. Avacta’s pre|CISION pro-drug approach is designed to reduce the systemic exposure of healthy tissues to the active chemotherapy, leading to improved safety and therapeutic index, potentially resulting in improved dosing regimens, better efficacy and better outcomes for patients. Once this approach is proven using Doxorubicin, it can be applied to a broad range of established chemotherapies, creating the next generation of oncology drugs which are better tolerated by patients. MT: What is Avacta’s pre | CISION technology and where does AVA6000 fit in to this? Avacta’s proprietary pre|CISION platform incorporates a substrate that is specifically cleaved by the protease fibroblast activation protein alpha (FAPα), which is at low background levels in healthy tissue and upregulated in most solid tumours. When modified with the pre|CISION chemistry, in its pro-drug form, a chemotherapy cannot enter cells and is therefore inactive until it encounters FAPα when the substrate is removed. This provides an activation mechanism to ensure localised release of chemotherapeutic agents from their pro-drug form in tumour tissue. The pre|CISION platform is highly specific to FAPα which therefore limits systemic exposure, improving the therapeutic potential and safety of these effective cancer therapies. AVA6000 is a pre|CISION pro-drug form of Doxorubicin and the first pro-drug based on our pre|CISION platform. Doxorubicin is a generic chemotherapy that is widely used as part of standard-of-care for several tumour types, though cumulative toxicity, particularly cardiotoxicity, limits its use. The AVA6000 trial offers the near-term opportunity to develop a safer form of Doxorubicin, whilst providing validation for the pre|CISION FAPα activation platform. MT: AVA6000 is the first therapeutic based on this technology. What opportunities does this technology offer for the wider drug discovery and oncology sector? If the pre|CISION platform mechanism of action is recapitulated in humans then this opens up the opportunity to apply it to a range of other chemotherapies to create safer and potentially more efficacious chemotherapies. Since FAPα is an extracellular enzyme, the pre|CISION platform also has potential to be used in the linker of a drug conjugate which provides extracellular release of the warhead in the tumour microenvironment. These are potential applications of the pre|CISION platform that Avacta is exploring in-house and through partnerships. MT: What are the expected results from these Phase I trials of AVA6000? The Phase I, open label, dose-escalation and expansion study has been designed to evaluate the safety, pharmacokinetics and initial therapeutic activity of AVA6000, administered Intravenously in patients with locally advanced or metastatic solid tumours. Results from the dose escalation part of this study is anticipated to read out in the second quarter of 2022. MT: What will this study mean for future tumour targeting? Harnessing the enzymatic activity of FAPα is in itself a form of tumour targeting – targeting the activation of a pre|CISION pro-drug to the tumour because of the upregulation of FAPα in most solid tumours. Utilising the pre|CISION platform in the linker of a drug conjugate allows this targeted activation to be combined with additional targeting of a a chemotoxin or radioligand to tumour cells through an antibody or Affimer against a tumour biomarker. With our collaborators at Tufts University Medical School, Avacta has developed this TMAC concept (tumour microenvironment activated drug conjugates) tumour targeting concept, which incorporates the pre|CISION substrate in the linker of a drug conjugates. A TMAC does not need to target an internalising cancer marker, as with conventional antibody drug conjugates, which raises the intriguing possibility of selecting the Affimer, or antibody, to target an immune checkpoint such as PD-L1. In this TMAC format, the drug conjugate not only harnesses the innate immune response to the chosen chemotoxin, but also provides support for the adaptive immune response through checkpoint inhibition, in a single drug entity. About the author Alastair Smith is Chief Executive of Avacta Group, he has been responsible for the management and strategic development of the company and has led the public and private M&A activities of the Group since the IPO on AIM which was completed via a reverse merger in 2006. He has a degree and PhD in Physics from Manchester University and, following a period of working in the US, took up a position at Leeds University in 1995. At the age of 38 he was awarded a Chair of Molecular Biophysics and had, over ten years, grew one of the leading biophysics research groups in Europe before he left his academic career in 2007 to focus full time on delivering value to Avacta shareholders.