Decompensation of liver cirrhosis and progression towards acute-on-chronic liver failure (ACLF) causes 1.2 million deaths/year. Microbiome is causally involved in cirrhosis progression and is for drugs the first interaction point with the patients. Drugs can alter the microbiome leading to unwanted effects or even facilitating their effects, but the microbiome metabolizes the drugs, shapes their effects and possibly determines the host response to drugs. As each person carries an individual microbiome, insight in these processes should help stratify or even personalize patient health care and treatment. The aims of MICROB-PREDICT are 1) to better understand the role of microbiome and the gut-liver-axis interactome with respect to microbiome functionalities, 2) to identify and validate microbiome-based biomarkers and signatures for personalized prediction of decompensation and ACLF, and response to treatment, 3) to design three new tests as easy-to-use tools and point-of-care, smartphone-connected nanobiosensors, and 4) to validate them in a randomized controlled trial. MICROB-PREDICT will assemble existing data and samples from major microbiome initiatives in hepatology (12 international studies, >10,000 patients), and enrich them with holistic and in-depth analysis using cutting-edge multi-omics technologies of host and microbiome from different body sites in samples of >1,000 patients collected in a longitudinal manner with sequential visits and controlling for confounders. MICROB-PREDICT results will foster more accurate, personalized risk stratification and significant steps towards personalized treatment of decompensated cirrhosis and ACLF. World-leading microbiome specialists, technology leaders and clinical experts make this a programme of scientific excellence; patient organisations (ELPA) and the European Association for the study of the Liver (EASL) will channel our results into a powerful dissemination, communication and exploitation programme.

Strongly associated with the epidemics of obesity and type 2 diabetes that are testing healthcare systems worldwide, Non-Alcoholic Fatty Liver Disease (NAFLD) is an increasingly common cause of advanced liver disease that is characterized by substantial inter-patient variability in severity and rate of progression. It is currently assessed by liver biopsy, an invasive, costly and risky procedure. The lack of noninvasive biomarkers has hampered patient care and impeded drug development by complicating conduct of clinical trials.The overarching aim of LITMUS is to develop, robustly validate and advance towards regulatory qualification biomarkers that diagnose, risk stratify and/or monitor NAFLD/NASH progression and fibrosis stage. This will be achieved through a goal-oriented, tri-partite collaboration delivering a definitive and impartial evaluation platform for biomarkers, bringing together: (i) End-users of biomarker technologies (clinicians with expertise in NAFLD and the pharmaceutical industry)? (ii) Independent academics with expertise in the evaluation of medical test/biomarker performance? and (iii) Biomarker researchers and developers (academic or commercial). LITMUS has the demonstrable capability to fulfil the IMI call remit. Built upon foundations laid by the EU-funded FLIP/EPoS projects and long-established, successful scientific collaborations amongst many of Europe’s leading clinical-academic centres, LITMUS is at a unique advantage due to its existing large-scale patient cohorts, bioresources and multi-omics datasets. Consortium members are internationally recognised experts with substantial relevant expertise supporting the program’s clear focus on biomarker identification, validation and accelerating EMA/FDA qualification. Thus, LITMUS is powered to provide clarity on biomarker validity for NAFLD at scale and pace: supporting drug development and the targeting of medical care and limited healthcare resources to those at greatest need.

Liver cirrhosis is a very common and severe chronic disease, responsible for high morbidity, impaired quality of life, major healthcare costs, and poor survival, causing an estimated 170,000 deaths per year in Europe. Liver cirrhosis is preceded by a long period of slowly developing, asymptomatic, liver fibrosis; most commonly caused by non-alcoholic fatty liver disease (NAFLD, related to obesity and type 2 diabetes), alcohol, and hepatitis B or C virus infection. There is no treatment available to reverse advanced liver cirrhosis. However, if fibrosis could be detected early, all of the major causes are still amenable to prevention and treatment. Early diagnosis of liver fibrosis in the general population is therefore crucial for the estimated 10 million Europeans with undetected liver fibrosis. The LiverScreen project aims to develop a targeted screening methodology to identify persons with asymptomatic liver fibrosis and cirrhosis among the general population. This methodology involves: 1) identification of groups from the general population at high risk of having chronic liver disease, 2) screening their liver stiffness with the innovative transient elastography (TE) technology (until now only validated in patients with known liver disease) for diagnosis, and 3) determining the right follow-up screening regime. Within the LiverScreen project 8 European countries will collaborate and perform research in over 34,000 subjects to develop the screening methodology and demonstrate its accuracy, clinical value, cost-effectiveness, acceptability, and potential to be implemented by healthcare systems throughout Europe. Using the LiverScreen program, diagnosis at an early stage can stop liver disease progression and have a subsequent long-term impact on liver disease morbidity and mortality and the associated societal burdens in terms of economic costs and health inequity. The estimated cost reduction ranges from €850 to €4,000 per quality-adjusted life-year gained.

Liver disease incidence is increasing and about 170K patients die from liver failure each year in Europe. In liver failure, the accumulation of protein bound toxins and increased susceptibility to infection cause multiorgan failure and death. Liver transplantation is the only treatment known to prolong the life but is limited by availability of organs. A clinically efficacious ‘liver dialysis device’ is an unmet clinical need. The ALIVER Consortium has developed and optimised a novel ‘liver dialysis device’, DIALIVE. The DIALIVE device is protected by world-wide patents and is based upon our discovery that (i) albumin, a circulating protein involved in detoxification is reduced irreversibly in function and (ii) endotoxemia contributes to increased risk of infection in liver failure. DIALIVE incorporates albumin removal and replacement and, endotoxin removal and is a TRL5. In animal models of liver failure, DIALIVE was shown to be easy to use, safe, reduced endotoxemia and, improved albumin and immune function and, prolonged survival. The ALIVER Consortium, which is comprised of experts in liver failure, SMEs and charities proposes to perform clinical trials of DIALIVE in patients with acute on chronic liver failure (ACLF). During the grant period a CE-mark will be obtained and the device will progress to a TRL7/8. Consultation with Regulatory bodies confirms that if the trials are successful, a CE-mark is highly likely. Grifols, a large plasma proteins company is a potential licensee of the technology if the studies proposed by the ALIVER Consortium are positive. We plan to take the project through regulatory and ethics approval and perform a study to define its safety in ACLF patients in 18 European hospitals; define health economic benefits to the EU and define a reimbursement strategy. The results will be disseminated widely and results exploited to benefit patients, EU healthcare system, create new jobs and grow healthcare Industry in Europe.

In Europe, about 30,000 people die every year from alcohol related cirrhosis, a form of chronic, non- communicable disease. The patients that are at highest risk of death are those with superimposed alcoholic hepatitis (AH) who do not respond to therapy and develop acute on chronic liver failure (ACLF), a newly described syndrome characterised by multiorgan failure. Treatment of ACLF is an unmet need. Based upon their clinical and pre-clinical studies, the A-TANGO consortium aims to perform Phase 2 clinical trials of a novel, patented and innovative therapeutic strategy by repurposing a toll-like 4 receptor antagonist (TAK242, Technology Readiness Level (TRL) 8), which targets inflammation, and combining it with granulocyte colony-stimulating factor (G-CSF, TRL9) that improves hepatocyte proliferation (G-TAK, TRL4). A successful trial will advance G-TAK to TRL8. Additionally, A-TANGO aims to discover novel biomarkers for patient selection and defining prognosis, building health economics models and reimbursement strategies to allow maximal dissemination and exploitation. The A-TANGO Consortium includes the inventors of G-TAK (UCL, Charité, ULEI and LUMC) and will deliver the project aims through EFCLIF, which has a network of 110 European hospitals. YAQ and HPX are SME’s that own the background IP and will ensure regulatory approval, study Sponsorship and drug supply. APHP and IMAC will deliver the economic models. Concentris will manage the project and together with EASL, CHX and ELPA will engage with patients, initiate widespread dissemination activities and allow exploitation of the results. Gender balance will be maintained throughout the project duration. A-TANGO will achieve the expected impacts of producing meaningful advances in clinical practice by reducing the mortality and improving the quality of life of patients with ACLF whilst reducing disease burden of individual patients and health care systems following validation in late stage clinical trials.