Drug repurposing can fill an important gap for rare disease patient groups with large unmet medical needs. In comparison to traditional drug development, drug repurposing reduces the time and costs for drug development, regulatory approval, and market authorization. Yet, we need to increase the efficiency of the drug repurposing pathway to provide broader access to new therapeutic modalities for larger groups of patients. SIMPATHIC’s main objective is to accelerate drug repurposing for rare neurological, neurometabolic and neuromuscular disorders. SIMPATHIC’s main accelerating innovation is the simultaneous drug development for groups of patients with different genetic diagnoses but overlapping neurological symptoms and molecular pathomechanisms. SIMPATHIC’s key outputs accelerating the drug repurposing pathway include: Standard operating procedures for culturing stem cell-derived neuronal cell models with proven relevance for clinical symptoms and amenable to high-throughput drug screens; New drug repurposing candidates with proven efficacy in advanced brain-on-a-chip and 3D brain organoid models, as demonstrated by reversal of molecular biomarker signatures and cellular readouts associated with clinical symptoms; Designs of innovative basket clinical trials to which patients with different disorders are recruited, utilizing and aggregating personalized clinical endpoints; A training module for patients and patient organizations to empower them as drivers of the drug repurposing pathway; Blueprints for intellectual property strategies, business models, regulatory dossiers and patient access strategies, developed in co-creation between all relevant stakeholders. SIMPATHIC’s proof-of-concept for the simultaneous development of repurposed drugs for multiple indications will show the path forward to development of personalized treatment opportunities for groups of rare disease patients in a cost- and time-efficient manner.

Development of a cure for rare cardiac diseases is a risky, costly and time-consuming process, which is hampered by insufficient insight into pathophysiological mechanisms of the diseases and lack of relevant disease models. The GEREMY consortium proposes to overcome this challenge by developing a gene therapy (GT) for inherited arrhythmogenic cardiomyopathy (ACM), by targeting the disease-causing PLN (non-desmosomes) and PKP2 (cardiac desmosomes) mutations. The GEREMY consortium will apply a unique parallel approach and investigate various promising GT approaches (oligonucleotide chemistries, gene editing and gene delivery). Also, the consortium will engineer disease models for proper assessment of therapeutic interventions and aims to provide in vitro & in vivo preclinical proof-of-concept for the GT. A significant benefit compared to current technologies is that the GT has the potential to be a curative treatment for rare cardiac diseases. Based on previous successes, GEREMY will target PLN & PKP2 as a roadmap of the technology. Restoring the primary defect in the PLN & PKP2 genes that cause the disease will lead to preserving or even restoring myocardial contractility. Through this approach, GEREMY will work towards a curative treatment of inherited ACM and likely other cardiomyopathies, which significantly reduces the healthcare burden. The project’s experts in preclinical research and cardiac genetics will deliver preclinical efficacy and safety data for the mutation correction. The partners with regulatory and clinical trial expertise (EXOM, EUF, NLHI) will prepare for immediate start of clinical trials upon project completion, and apply for orphan drug designation. EUPATI, a patient organisation and KUL ethics partner will ensure that the project is continuously aligned with patient needs and ethical perspectives. The whole consortium will contribute to communicate an disseminate the results to ensure maximum exploitation of this breakthrough technology.

FACILITATE is a project built on a patient-centered, data-driven, technological platform where an innovative data sharing and re-use process allows the returning of clinical trial data to study participants within a GDPR compliant and approved ethical framework. FACILITATE starts-off by providing clear rules in a trusted ethical, legal and regulatory ecosystem before engaging patients as data generators. This avoids the current situation where clinical data are siloed in separate repositories without any possibility to be used beyond their original single-sided purpose. FACILITATE will provide the technological solutions to comply with GDPR in medical research by building on the empowered stakeholders' willingness to share and re-use their data. The FACILITATE Consortium was constituted by drawing from a broad range of capacities to tackle the ambitious challenges related to future clinical trials, such as preventive, long-term and real-world evidence trials. The Consortium took an innovative approach to the data return to study participants by asking them what they needed to be implemented to feel in a trusted ecosystem. This required all Consortium participants to leverage on their existing networks to bring together stakeholders at all levels in the decision-making chain, including patients, healthcare professionals, software designers, clinical trials repositories processors and controllers, ethicists, lawyers and other active regulators. Having obtained a consent on the data portability FACILITATE will re-use and cross-reference them with those contained in other repositories including RWE data captured across multiple settings and devices. FACILITATE will last 4 years and will participate in the extended Pilot on Open Research Data of Horizon 2020. Its strategy represents a unique and innovative opportunity for medicines drug development and regulation to better understand the clinics of diseases, and to evaluate the effectiveness of products in the healthcare system.

Europe generates real world health data (RWD) that has the potential to inform the development and evaluation of medicines and medical devices. However, multiple barriers remain that limit the access, analysis, interpretation, and use of RWD, hampering its use. Additionally, the limited uptake of existing guidelines for the generation and use of real world evidence (RWE) adds complexity in the use of RWD to inform decision making. The GREG consortium will leverage the learnings of previous and ongoing key RWE initiatives to fill these gaps by generating, pilot-testing, and disseminating evidence-based guidance and tools for the use of RWE to inform the development and evaluation of medicines, medical devices, and combinations. To achieve these goals, we will work with key stakeholders to iteratively test and improve our guidance and tools, backed by case studies from previous successful and unsuccessful examples. We will engage with the most relevant European RWE initiatives and access the largest network of RWD partners in Europe, namely the European Health Data and Evidence Network (EHDEN) through our partner, the EHDEN Foundation. Additionally, we will provide multi-stakeholder gatherings (including patient and public representatives) to promote the dissemination, adoption, and implementation of RWE for decision-making in Europe. Our public and private partners will co-create use cases working closely with key regulatory and health technology experts in bespoke fora. These will be used initially to evaluate existing guidelines, and later to pilot-test the GREG guidance and tools. Our outputs will include training for all involved stakeholders on the use of our guidance and tools, and practical templates to facilitate regulatory and health technology/payer submissions. Together, these will accelerate access to better medicines and medical devices for European citizens.

Coronary artery disease (CAD) is caused by the pathological process in which fat, cholesterol and calcium accumulate on the arterial wall. It is the leading cause of mortality in the world, affecting in 2019 about 200 million individuals or 2.5% of the global population and resulting in over 9 million deaths annually. The prevalence of CAD in the European Union (EU) reached 5.11% in 2019 . As a result, CAD-related deaths topped 973,000 in the EU in 2019. CAD incidence is expected to rise further due to the increased prevalence of risk factors including obesity, diabetes, and increasing age. For a patient with CAD, the care pathway still involves enormous variability and complexities. Inefficiencies and challenges in the treatment pathway are associated with poorer patient outcomes including recurrent cardiac events, incomplete revascularization in complex patients, and increased risk of mortality in patients with both acute and chronic CAD. Due to the low sensitivity or specificity of the standard diagnostic tests, 60% of CAD patients unnecessarily undergo an ICA, as they are found to have non-significant coronary stenoses and do not require revascularization. Coronary Computed Tomography Angiography (CCTA) uses X-ray technology and computer processing to create a detailed 3D image of the coronary arteries, revealing the degree of lumen obstruction. It provides non-invasive access to the coronary anatomy, also for asymptomatic patients who would normally not undergo invasive coronary angiography (ICA). Current guidelines adopted in the US, EU, and the UK recommend CCTA as a first-line test for evaluation of CAD, positioning it as a "gatekeeper" to the Cath lab. In COMBINE-CT, we will deliver a fully automated, vendor agnostic CCTA-enabled workflow for chronic CAD patients, covering diagnosis, treatment, and follow-up. COMBINE-CT will close the gaps in the existing workflow for the treatment of chronic CAD, to improve hospital efficiency and patient outcomes. AI-powered CCTA algorithms will enable definitive ischemia diagnosis, accurate patient stratification and efficient planning of the interventions, as well as patient specific follow-up. While our focus on CAD is justified by the large patient population, the CCTA-enabled diagnostic accuracy and seamless workflow, backed by the clinical evidence generated in five multicentre clinical trials, will be directly transferable to other clinical domains using CT. Interdisciplinarity is intrinsically built in the design of the COMBINE-CT consortium, combining expertise in cardiology, cardiovascular radiology, interventional cardiology, cardiac surgery, pharmacology – with expertise from engineering (medical imaging) and AI. The public-private partnership in COMBINE-CT integrates top knowledge on several medical disciplines (cardiology, radiology, interventional cardiology) with engineering, AI, design expertise - as well as the involvement of health economists and patient organizations, to fill in the gaps of the current CAD clinical pathways and prepare the ground for the imminent high-volume CCTA needs, beyond the research hospital setting. Clinical partners represent more than half of the COMBINE-CT consortium, ensuring access to large cohorts for stable CAD patients. COMBINE-CT will also lay the ground for further research that is likely to trigger a paradigm shift towards the use of imaging markers in the medical treatment evaluation and clinical trial design.