The overarching aim of the COVend Research and Innovation Action is to deliver a new effective precision therapy against SARS-CoV-2 for the clinical management of COVID-19 during mild and moderate stages, including the prevention of disease progression to severe illness. We aim to achieve this by testing a promising candidate, the peptide FX06, in a placebo-controlled, multi-national ph II/III study in moderate cases of COVID-19.
FX06 does not belong to any known drug class and targets the endothelium, which is affected directly or indirectly by the virus. Based on animal models, FX06 has considerable therapeutic potential for all diseases and pathological conditions associated with increased vascular permeability. FX06 binds to vascular endothelial (VE)-cadherin, preventing the transmigration of leukocytes.
Proteomics, lipidomics, and metabolomics of patient-derived blood samples will provide a profound understanding of the interplay between the systemic inflammation of the endothelium caused by SARS-CoV-2 infection and the – also systemic – action mode of FX06. Newly identified effector molecules will be studied in vitro and profiling data will be used to train AI for clinical application. Multi-Omics revealed parts of the molecular signature of COVID-19 and the host immune response and were thus suggested for prognostic applications and drug target discovery (Li et al. 2021, Su et al. 2021).
Primary human pulmonary endothelial cells and an endothelial cell line will be incubated in the presence or absence of FX06. The inflammatory/immunological activation status of endothelial cells will be tested in flow cytometric analyses and investigated under shear stress conditions. Our partners from UCD have already achieved major breakthroughs in the development of assays for the characterisation of endothelial cells (ECs), transendothelial migration and gene expression upon stimulation with COVID-19-triggered cytokines. FX06 has shown beneficial effects under multiple conditions in the context of endothelial hyperinflammation models in vitro.
AI-based automated characterisation of the study cohort using advanced unsupervised clustering methods will integrate a wide variety of data sources will such as Omics, vital signs, and open registry data. A directed supervised approach will be used to train specific machine learning models that will provide new insights into patient properties and consider the time dynamics of the patient state to optimise and personalise treatment planning.
Market access is facilitated by an extensive health economic assessment performed by our partners from UMCG. The sequence of regulatory steps and the assessment criteria in the reimbursement process varies across the countries that take part in the IXION trial. After a reimbursement decision has been made, the actual use and funding of inpatient medicines are in most countries dependent on a positive assessment by individual hospitals. A descriptive analysis of both national methodological guidelines for the conduct of health-economic evaluations as well as potential barriers and facilitators to the uptake of FX06 as a hospital drug addressed the need for a flexible health economic model. A flexible model will accommodate health economic analysis of FX06 in the context of various capillary leak disorders and country-specific policies.