Preclinical type 1 diabetes (T1D) research has made important advances in recent years, but less progress has been made in translating findings from in vitro and animal models into effective clinical interventions. INNODIA aims to achieve a breakthrough in the way in which we study T1D to enable us to move closer towards prevention and cure of T1D. To this end, INNODIA joins together the leading European experts from the fields of basic and clinical T1D research, four leading pharmaceutical companies with strong expertise in the discovery and development of diabetes medicines and the two leading public organizations involved in T1D research into one comprehensive collaborative consortium. The clinicians in INNODIA oversee T1D registries and have access to large populations of children and adults with T1D and family members at increased risk of developing the disease. The basic science researchers are experts in beta-cell pathophysiology, immunology, biomarker discovery, bioinformatics, systems biology and clinical trial design. INNODIA will accelerate understanding of T1D through coordinated studies of unique clinical samples and translation-oriented preclinical models. This should deliver novel biomarkers and interventions for testing in appropriately designed trials, to be developed in active collaboration with regulators and patients. INNODIA provides access to unique historical biorepositories and will create the Clinical Sample Network, a clinical EU infrastructure to recruit T1D subjects at diagnosis and at-risk relatives. These individuals will be deep-phenotyped and will provide biosamples, allowing the establishment of a ‘living biobank’ of subjects consented for recall. They will be characterized using standardized clinical, genetic and metabolic phenotyping procedures, including prospective, longitudinal sample collection to facilitate novel biomarker discovery. Diverse biological samples (blood, plasma, serum, urine, stools, etc.) will be collected at

Building on the strong foundations of INNODIA, with its unique, Europe-wide clinical and basic research network for the study of type 1 diabetes (T1D), we propose in INNODIA HARVEST an ambitious program which aims to prevent and arrest T1D via focused objectives targeting consolidation and innovation. First, we will consolidate the INNODIA clinical network as the reference point for conducting studies to prevent or arrest T1D. We will transform our standardized clinical and bioresource platforms into a high-performance clinical trial network, running academic and industry-driven trials alongside small, mechanism-centric, biomarker-rich intervention trials to examine pathobiological pathways to T1D. INNODIA HARVEST will conduct two large studies to arrest T1D at its onset, one academia-driven, beta-cell focused (VER-A-T1D, verapamil) and one industry-driven, immune-focused (Iscalimab-study). We will exploit our original INNODIA Master Protocol allowing novel adaptive trial design to introduce combination therapies that build on complementary mechanisms. Second, we will extend our study design strategy by introducing novel biomarkers, both clinical (continuous glucose monitoring) and experimental (microbiome analysis) to deconvolute disease heterogeneity and identify new endpoints to accelerate identification of effective therapeutics. Third, we will use ‘disruptors’ in small mechanistic studies to channel innovation from clinic to basic research through a reverse immunology and reverse beta-cell biology approach. Finally, we will implement new discovery pipelines for future therapeutics, exploiting tools such as iPSC-derived islet-like cells to promote next generation target identification and drug development. As in INNODIA, the voice of people living with T1D and their families will hold a central place in INNODIA HARVEST to drive implementation of new, patient-proximal outcomes, shape our clinical trials, and bring about a meaningful change in disease perspective. A major objective of INNODIA Harvest is the execution of at least two new phase 2 trials (studying Verapamil (VER-A-T1D) or Iscalimab (CCFZ533X2207)). Considering the expected time to first patient-in as preparations for trial start can only be initiated after the start of the Action and possible fluctuating recruiting rates, due to the intercurrent COVID epidemic, there is a risk that INNODIA HARVEST will not be able to completely finalize the clinical trials, fully analyse the biomarkers collected and publish the results in the initially proposed 24 months duration. To ensure the finalization of the clinical trials and corresponding full execution of the given budget including eligibility of EFPIA in-kind contribution we propose to extend the duration of the Action from 24 to 36 months.

EDENT1FI is a unique and timely project building and operationalising an open platform for general population screening of children/adolescents for type 1 diabetes (T1D) throughout Europe. The case is compelling: T1D is a common chronic disease affecting >1 in 300 children or adolescents. Decades of European research have signposted the step-wise nature of T1D development and generated tools for early diagnosis, monitoring and disease modification. EDENT1FI now positions Europe as the leader in early interception of T1D. Our goals are to identify individuals at earlier, pre-clinical stages, dramatically reducing clinical severity at T1D diagnosis and providing the opportunity for interventions with disease modifying therapies to delay or prevent clinical T1D. Spurred by the success of our collaborations in model European childhood screening activities and clinical networks in GPPAD and INNODIA, EDENT1FI will: establish harmonised islet autoantibody surveillance programmes to screen 200,000 children/adolescents across Europe; assess the psychosocial, medical and economic impact of screening in diverse European health systems/populations including underserved families; use state of the art metabolic sensors and biomarkers to optimise monitoring schedules for early-stage (pre-clinical) T1D aligned to maximising compliance and identifying disease progression strata; design SMART trials to expedite evaluation of disease modifying therapies; and inform and educate the public, healthcare professionals, and regulatory authorities of the new paradigms in T1D diagnosis and care. To achieve this, EDENT1FI assembles academic, clinical and industry expertise in screening, clinical care, biomarkers, machine learning, population outreach, ethics, regulatory affairs and policy to accelerate evidence-based early T1D screening into regular healthcare in Europe. The success of these activities will promote early diagnosis and prevention pathways for other chronic childhood diseases.