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.

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

The ELR SCAR project aims to complete preclinical validation of a novel biomaterial, an elastin-like recombinant (ELR) hydrogel, to prevent scar tissue formation in the heart following myocardial infarction (MI), commonly called a heart attack. MI is the endpoint of ischaemic heart disease (IHD). In Europe, the highest rates of IHD worldwide equal ~26.5 million patients. Standards of care interventions after MI have serious limitations in treatment efficacy (many patients are still at risk of developing heart failure) and patient safety. There is a clear medical need for new treatment solutions that prevent scar tissue formation and irreversible cardiac remodelling. Our robust preclinical dataset so far indicates that the ELR hydrogel has this promising functionality via multiple unique characteristics: it provides selective cell adhesion to the endocardium, providing a barrier to scar tissue formation; it offers high biospecificity to the ischaemic microenvironment, and it has an enhanced biodegradability, allowing for safe disintegration in the body. To facilitate endocardial delivery of the ELR hydrogel, we will develop a minimally invasive endocardial catheter in this project. Both components (hydrogel + catheter) will be advanced to the preparedness level for a first-in-human (FIH) validation study for the application as therapeutic intervention post-MI (to be performed after the project). In addition, we will develop the regulatory and IPR strategies in preparation for this clinical validation step. Considering the high societal impact of ischaemic heart disease (IHD) and MI, we will also develop a solid health economic evaluation of possible savings and patient benefits. ELR-SCAR will transform and fundamentally improve clinical practice, resulting in reducing the enormous burden that MI and its leading cause, IHD, place on society and the individual patient.

Sudden cardiac death (SCD) is a major public health problem accounting for ~20% of all deaths in Europe with an estimated yearly incidence of ~350-700,000, often in patients with previous myocardial infarction (MI). In SCD, the heart suddenly and unexpectedly stops beating. If untreated, the patient dies within minutes, but SCD can be successfully prevented by an implantable cardioverter-defibrillator (ICD). The ICD is highly effective, but is associated with potentially severe complications and high healthcare costs. Based on historical evidence, guidelines recommend prophylactic ICD implantation in post-MI patients with left ventricular ejection fraction (LVEF)≤35% to prevent SCD. However, only a minority of these patients will ever need the device. In addition, in absolute numbers the majority of SCD cases occurs in patients with LVEF>35% who are currently not considered for prophylactic ICD. Due to the inherent risks and considerable health care expenditures, a personalised treatment approach for ICD implantation is urgently required. Using state-of-the-art methods and large clinical datasets from established international cohorts and registries across different European geographies, PROFID will develop a clinical decision support tool (risk score) to predict the individual SCD risk and identify those post-MI patients that will optimally benefit from an ICD. Two parallel randomised clinical trials will validate implementation of the risk score to determine ICD implantation, while health economic analyses will assess its economic impact on health care systems. A software tool for clinical use of the risk score will be implemented, and a pilot run in 3 European regions with participation of insurance companies and authorities. The unique composition of the consortium with key opinion leaders, patient organisations, large hospital chains, payers, policy makers and state authorities across Europe, will ensure implementation into routine clinical practice.