Authors: Luka Hiti, Maša Kandušer, Tijana Markovič, Tilen Burnik, Mitja Lainščak, Emil Pal, Jerneja Farkaš Lainščak, Irena Mlinarič-Raščan

Poster

Cytokine storm, a COVID-19 complication, is a life-threatening systemic inflammatory syndrome involving the uncontrolled secretion of cytokines, which in severe cases leads to systemic organ failure and death. Especially in the first year of the COVID-19 pandemic, effective treatments for cytokine storm were not available. With the urgent need for treatment options, drug repurposing came to the forefront as it could cut the normal time from drug discovery to registration by more than two thirds. The first step in drug repurposing is compound screening, for which good in vitro cell models are necessary. We present here a novel in vitro cell model for evaluating the potential of compounds in decreasing the secretion of cytokines: immortalised B-lymphocytes, known as lymphoblastoid cell lines (LCLs). For drug screening we selected a set of compounds based on literature search or our previous research. We compared LCL to an established in vitro cytokine release model, whole blood. Whole blood represents phenotypes of different donors, contains different cell types, but it can only be used for one analysis and repeated sampling is needed. While there already are other commercial in vitro cell line models for cytokine secretion (e.g. THP-1, Jurkat), they represent only one phenotype. To cover different phenotypes, we have prepared a biobank of LCLs derived from 71 reconvalescent COVID-19 donors with differing severity of disease. Our results on a selected set of compounds indicate that the trend of cytokine secretion suppression is comparable between whole blood and LCL. The most promising results for drug repurposing were obtained for dexamethasone and MEK1/2 inhibitor trametinib. This supports the use of LCLs as a suitable in vitro cell model and as a good personalised medicine platform for cytokine-release related compound screening, since our LCL COVID-19 patients derived biobank accounts for interindividual differences.

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Authors: Dalma Hosszú, Máté Pálfi, Zsuzsanna Petykó, Heleen van der Meer, Pan Pantziarka, Patricia Vandamme, Dunja Huijbers, András Inotai, Marcell Csanádi

Poster

Conventional valuation strategies for new medical entities are often not appropriate (do not capture all aspects of short and long-term value) to apply to drug repurposing, and there is a lack of broadly accepted methods for assigning quantifiable values to patient and societal benefit. REMEDI4ALL aims to create a range of incentives and funding opportunities to engage funders with drug repurposing (DR) projects. One key activity is to develop standardized assessment criteria for such projects. This will be in the form of a tailor-made and flexible tool that can encompass a wide range of assessment criteria more appropriate to the challenges of DR.

We performed a systematic overview of two major information sources: documents used by research funders (e.g. funding call application evaluation forms) and published literature. Potential funders were identified from the Funders Network, established by ZonMw within REMEDi4ALL. Such organizations were asked to share their relevant call documents, whether publicly or internally available. Scientific and grey literature were queried using PubMed and Google Scholar with additional publications made available from other REMEDi4ALL activities. An initial list of assessment criteria was created consisting of the raw texts selected from the queried data sources. Multiple criteria overlapped, differed in minor ways or were conceptually similar despite radically different wording. An iterative method was applied to group similar criteria together and to formulate concise and inclusive definitions in order to create a smaller fundamental set of assessment criteria. These were reformulated until a complete set of criteria that can conceptually include all the detailed collected data was established. Finally, based on the available data, a concise definition was attached to each criterion.

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Authors: Alessia Antonella Galbussera, Laura Fiorenza, Adrià Fernández-Torras, Jordi Quintana, Alessandra Leone, Alfredo Budillon, Mauro Tettamanti and Maddalena Fratelli

Poster

REMEDI4ALL is studying the repurposing of valproic acid (VPA) and simvastatin (SIM), administered on top of standard-of-care chemotherapy for metastatic pancreatic cancer. The two drugs are widely used and generally safe. However, we decided to evaluate the safety aspects of their combination using real-world data (RWD). We analyzed Lombardy Region’s administrative database (10M inhabitants). Healthcare in Italy is public, so the data are acquired for administrative and reimbursement purposes. Records contain information on sex, age, drug dispensation, hospital admissions together with primary and secondary diagnoses, ambulatory specialist visits and exemption registries. Subjects that acquired at least one package of VAL or SIM in 2015-21 without any package in the previous 5 years entered the cohort. More than 7,000 patients were treated with both drugs. Hospital admissions and outpatient visits showed no significant increase in these patients as compared to those in patients taking either drug individually. We also analyzed drug discontinuation rate, assuming that any side effects would lead to interruption of the treatment. The discontinuation rate of SIM was only slightly higher in patients with prior use of VAL than in those taking SIM only (HR 1.05, 95% CI 1.01-1.09). Conversely, there was a considerable decrease in the discontinuation rate of VAL in patients who were already taking SIM (HR 0.77, 95% CI 0.74-0.79). In parallel, we explored the post-marketing reports of adverse events (AEs) from four databases, which have been standardized, de-duplicated and corrected for masking effects in the CLARITY PV technology platform. Reassuringly, AE levels were generally lower in patients taking both VAL and SIM when compared to monotherapy, in agreement with the lower discontinuation rate observed in Lombardy. We conclude that there are no increased safety concerns in the patients taking both drugs. These results underline the importance of RWD in drug repurposing.

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Authors: Judit Baijet, Abby Stock-Duerdoth, Claudia Fuchs, Eve Hewitt, Virginie Hivert, William May, Rick Thompson

Poster

IDrug repurposing interest is steadily increasing in a variety of areas such as policy, regulation, funding and research. Although a huge amount of progress has been made in pushing forward this innovative opportunity in the drug development field, we frequently lack meaningful, efficient and effective patient centric perspectives to address unmet medical needs. REMEDi4ALL, the EU-funded multi-year initiative that aims at building a sustainable European innovation platform to enhance the repurposing of medicines for all, is positioning the patient’s voice and experience at the heart of every repurposing project and empowering them as true co-creators. To deliver on this mission, REMEDi4ALL is embedding patient engagement in all its four demonstrator projects as a core and essential principle for a patient-centric approach to drug repurposing. With the support of a dedicated and experienced patient engagement team established within the consortium, patient champions are identified and onboarded for every repurposing project to represent the patient community and make sure patients’ insights are taken into consideration. Similarly, patient advocacy groups are set up to support patient champions and to help shape the repurposing project for the benefit of the patient community. Through topic-specific multi-stakeholder meetings, REMEDi4ALL is also setting in a true collaborative environment bringing all stakeholders together to discuss different approaches to specific subjects on the drug development realm. REMEDi4ALL will also support patients and all the stakeholder groups with a comprehensive education and training portfolio designed to upskill, empower and build capacity among the whole drug repurposing ecosystem.

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Authors: Judith Cohen, Mahboobeh Haji Sadeghi, Keith Pugh, Bronwen Williams, Sarah Sumpter, Francesca Gurioli, Maria Gnoli, Alice Moroni, Martina Piccini Leopardi, Clara del Coco, Luca Sangiorgi, Nicholas Bishop

Poster

The MOI-A demonstrator (10.4) project within the REMEDi4ALL Consortium is assessing the repurposing of losartan in adults and older adolescents with osteogenesis imperfecta, an inherited form of bone fragility, caused in the majority of cases by mutations in one of the two genes encoding type I collagen. We have encountered challenges due to the variation in regulatory processes across national boundaries. We report on these issues with the expectation that future studies will be able to proceed more swiftly. Sponsorship agreement: discussions covered whether to have one sponsor with a legal-representative in the partner country, but the final decision was to develop a co-sponsorship agreement. Protocol preparation and regulatory approval: we decided to use one master protocol across both countries ensuring that the same procedures for treatment and outcome measures are followed. Availability of the IMP: we were unable to source one product that could easily be supplied in both countries and decided to use two different products. We had to check that they had identical constituents and agree which of the SmPCs from the 2 different brands would be used as the reference safety information (RSI). Reporting of SUSARs approaches in both countries: to ensure that we can comply with pharmacovigilance guidance from the competent authorities we considered different approaches to reporting of SUSARs. The UK Sponsor will report all the study SUSARs to the MHRA and the Italian Sponsor will report all the study SUSARs to EVCTM/AIFA. Database arrangements: patients will be randomised from one central randomisation system, and data will be collected in one central database provided by the UK to enable streamlined study oversight. We will present the current status of each of these areas with details of the discussions between the study team, regulatory authorities and REMEDi4ALL research development team (RDT) and the eventual solutions.

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Authors: Jordi Carreras-Puigvert, Martin Johansson, Malin Jarvius, Jonne Rietdijk, Polina Georgiev, Maris Lapins, Anders Larsson, Dan Rosén and Ola Spjuth

Poster

Phenotypic morphological profiling approaches, especially using Cell Painting, are gaining momentum as a powerful technology for compound profiling, mechanism of action (MoA) elucidation, safety, toxicology, disease modelling, and drug discovery. At the Pharmaceutical Bioinformatics (https://pharmb.io/) group at Uppsala University in Sweden, we have set up an automated lab and e-infrastructure to automatically perform Cell Painting and morphological profiling experiments. We combine phenomics (large scale morphological profiling), AI and automation for academic drug discovery, MoA prediction, as well as chemical and environmental toxicants profiling. In addition, as part of the Chemical Biology Consortium Sweden, we have profiled a drug repurposing library of 5270 annotated drugs and compounds that can be used for MoA investigation. Our lab has one of the largest morphological capacity and expertise in Europe and we strongly believe in the power of morphological profiling for drug repurposing, for which we are involved in several projects within REMEDI4ALL. We intend to continue exploring and profiling different disease models to be used in drug repurposing campaigns.

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Authors: Aron Schulman, Juho Rousu, Tero Aittokallio, Ziaurrehman Tanoli

Poster

Drug-target interactions (DTIs) hold pivotal role in drug repurposing and elucidation of drug mechanisms of action. While single-targeted drugs have demonstrated clinical success, they often exhibit limited efficacy against complex diseases, such as cancers, whose development and treatment is dependent on several biological processes. Therefore, a comprehensive understanding of primary, secondary and even inactive targets becomes essential in the quest for effective and safe treatments for cancer and other indications. The human proteome offers over a thousand druggable targets. Yet, most FDA-approved drugs bind with only a small fraction of disease targets. This study introduces an attention-based method to predict drug-target bioactivities for all human proteins across seven superfamilies. Nine different descriptor sets were meticulously examined to identify optimal signature descriptors for predicting novel DTIs. Our testing results demonstrated Spearman correlations exceeding 0.72 (P 0.57 (P<0.001) for most superfamilies. This justifies the robustness of the proposed method for predicting novel DTIs. Finally, we applied our method to predict missing activities among 3,492 approved molecules in ChEMBL-V33, offering a valuable tool for advancing drug mechanism discovery and repurposing existing drugs for new indications.

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Authors: Marianna Tampere, AdelinnKalman, JonneRietdijk, Hanna Axelsson, Duncan Njenda,Elin Asp, Maris Lapins, Kun Qian, Flavio Ballante, Ola Spjuth, Jordi Carreras-Puigvert, Brinton Seashore-Ludlow and PäiviÖstling

Poster

Today, the majority of screening methods evaluate the drug activity on a given virus while neglecting the host mechanisms and responses to the virus infection. New approaches are hence needed to identify novel or repurposed drugs to treat deadly viral infections. Here, we have investigated the antiviral activity of 5200 compounds from the SPECS drug repurposing library using distinct screening campaigns on; 1) host cell morphology changes by the phenomics assay Cell Painting 2) specific antibody-detection of SARS-CoV-2 infection rate and 3) the current standard cytopathic effect method. We demonstrate how SARS-CoV-2 infection induced a specific phenotypic signature in Vero E6 cells, which was reversed by assay controls such as remdesivir. Our unbiased host-focused approach identified additional 324 compounds with antiviral activity against SARS-CoV-2. To further study the host response during infection, we quantified the subcellular localization and expression of 602 host proteins using antibodies from the Human Protein Atlas. We identified phenotypic responses to SARS-CoV-2 infection in 97 proteins. Finally, to broaden the paradigm of how antiviral therapies are identified we aim to combine these host-focused screening approaches. Our preliminary analyses have identified 3 host proteins linked to 3 compounds that reverse the virus-specific phenotype, which all represent novel drug repurposing candidates against SARS-CoV-2. Taken together, these findings illustrate a new host-centric approach for the discovery of antivirals and could be applied for other emerging or re-emerging viruses.

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