Periodic Reporting for period 1 - TRANSBIO (A BIOmarker-based assay for prognosis and monitoring in renal TRANSplantation) Periodo di rendicontazione: 2015-11-01 al 2016-03-31 Sintesi del contesto e degli obiettivi generali del progetto BioHope is a leading biomedical company specialized in the development of novel diagnostic tools and advanced therapies for clinical management of organ transplanted patients. Thanks to the wide experience in molecular biology and medicine of the company´s team and the extensive research performed by the company in the field of immunology, BioHope has developed and patented a disruptive tool for efficient global clinical management of patients undergoing a kidney transplant. This patented technology is the basis underlying the TRANSBIO project. THE NEED BEHIND THE TRANSBIO PROJECT End-stage kidney disease (ESKD) is the last stage of a chronic kidney disease, which if not addressed leads to premature death and, although it can be addressed by dialysis, kidney transplantation is the preferred treatment due to better survival rates, improved quality of life and cost efficiency. However, although surgical techniques and postoperative care have greatly advanced, renal transplantation is not empty of challenges. The most important challenge is to achieve the long-term survival of the transplanted organ (also known as graft or allograft). Graft survival depends on the ability of the recipient of not rejecting the “foreign organ”. Rejection is a naturally occurring process triggered by a biological response of the immune system, which main function in the body is to defend it against infectious organisms and other invaders. As such, the immune system is prepared to reject a “foreign organ”, something that is nowadays prevented by prescribing immunosuppressive therapies (drugs that suppress/reduce the effectiveness of the immune system) to the patients for their whole life. However, although immunosuppressive therapies have represented a huge step forward in organ transplantation, their use still entails important problems. On one side, suppressing the immune system implies severe side effects like opportunistic infections, cancer and other severe pathologies. On the other side, even under immunosuppressive therapies, about 50% of transplanted kidneys are lost during the first 10 years and this is because of an immune response usually described as chronic rejection. Therefore, the major challenges in ESKD deal with avoiding the side effects associated with immunosuppressant drugs and avoiding chronic rejection. The key question is…how this can be made possible? To answer this question, we should first explain that patients undergoing a kidney transplant can show 3 different main immune response profiles in the long term (~10 years after transplantation):A) Classical response (~40% patients): graft is not rejected but requiring immunosuppressive therapy for the whole patient´s life. B) Chronic rejection (~50% patients): long-term loss of function in transplanted organs, even under immunosuppressive therapy. C) Operational Tolerance (~10% patients): patients who develop immunological unresponsiveness (tolerance) towards graft, so for whom the immunosuppressive therapy can be reduced or withdrawn.For the 40% of patients with a classical response, immunosuppressive side effects could be reduced by adjusting the treatment to the actual patient needs. For the 50% of patients, whose outcome is chronic rejection, this could be prevented by the early identification of this phenomenon and adjustment (increase/change) of immunosuppressive therapy. For the 10% of patients showing an operational tolerance, immunosuppressive drugs could be gradually reduced or withdrawn without compromising graft survival. However, all these solutions cannot be currently implemented in the clinical routine because of the lack of effective means for monitoring allograft function and rational based approaches towards selection of the optimal immunosuppressive therapy. THE TRANSBIO PROJECT CONCEPTIn the TRANSBIO project we aim at bringing to the healthcare market a novel tool for efficient global clinical management of patients who have undergone a kidney transplant. Our patented technology is based on a non-invasive blood test that will provide a double functionality for clinical management of renal transplantation: FUNTIONALITY A: MONITORING AND DIAGNOSTICS FOR:a) The early identification of patients at risk of chronic rejection, who might require an increase of immunosuppression or a change in the immunosuppressive programme prescribed, so enabling the clinicians to make early decisions on therapy adjustment to avoid graft rejection.b) The early identification of patients under feasible immunosuppression reduction, due to the development of any clinically significant operational tolerance, enabling a gradual withdrawal of immunosuppression and avoidance of severe side effects for these patients. FUNTIONALITY B: COMPANION DIAGNOSTICS to support clinicians in the determination of the optimal combination/posology of immunosuppressant drugs to reduce risk of organ rejection in all cases and enabling a reduction of the undesired side effects of an ineffective immunosuppression. BioHope has already performed the basic research and we have determined the project concept feasibility. In collaboration with renowned experts in Nephrology along Europe, in the TRANSBIO project we seek performing a complete clinical validation study to prove the clinical usefulness of our patented technology, get the regulatory approval for commercialization and bring our product to the healthcare market. Objectives of the Phase 1 projectThe TRANSBIO project is absolutely pivotal for BioHope as the key innovation project to boost the company´s growth over the next years. Therefore, the ultimate objective of this Phase 1 project was to perform a detailed analysis of the overall project feasibility (commercial, technical/scientific and financial points of view) so to undergo the next phases towards the market under a minimum risk scenario. The objectives we planned for this Phase 1 project were the following: A) Commercial feasibility objectives: To validate our market hypothesis with key opinion leaders, so to make sure the TRANSBIO project will find the expected market acceptance. To perform a comprehensive market analysis in order to determine the priority geographic markets to enter, the market barriers and drives, the competitive landscape and the key stakeholders to get involved for the success of TRANSBIO in the marketplace. To analyse the market opportunity by performing an in-depth analysis of End Stage Kidney disease and renal replacement therapy epidemiology (total market size for TRANSBIO). To define the optimal go-to-market strategy based on the outcome of the aforementioned objectives. B) Technical/scientific feasibility study objectives: To create a network of hospitals (Nephrology Units) around Europe as the partners with whom to perform the complete clinical validation study we are planning for the TRANSBIO project. To search for appropriate partners (besides hospitals) as collaborators in the TRANSBIO project for turning our patented technology (prototype) into a ready-to-market solution. To design the clinical validation study according to the feedback received from Key Opinion Leaders, so to guarantee the most rigorous clinical standards are met in the TRANSBIO project towards the market. To prepare the ethics committee documentation and request the approval by regulatory bodies before conducting the clinical study. C) Financial feasibility study objectives To carefully analyse the investment requirements to reach the go-to-market stage. To prepare a 5 years business plan for TRANSBIO commercialization by analysing different scenarios. To determine the TRANSBIO project profitability for different scenarios. Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti During this Phase 1 project, we have performed an in-depth assessment of the feasibility of our business innovation project from different perspectives: commercial, technical /scientific and financial. Below we details the work activities performed in each study category:COMMERCIAL FEASIBILITY STUDY: We have successfully engaged some of the most important KOLs all over Europe in the TRANSBIO project and nowadays that are part of our Scientific Advisory Board. We have successfully validated the market hypothesis by a survey conducted among KOLs (top Nephrologist) in Europe. We have performed an extensive study of End stage kidney disease and renal replacement therapy epidemiology worldwide. This has enabled us to quantify the total market for the TRANSBIO solution.We have performed an in-depth market analysis: market features, barriers and drivers, analysis of competitors and commercial risk assessment. We have defined a rational go-to-market and expansion strategy. TECHNICAL/SCIENTIFIC FEASIBILITY STUDY We have determined the feasibility of using the TRANSBIO test with a double functionality: A) monitoring and diagnosis for the early identification of patients at risk of chronic rejection or showing signs of operational tolerance and B) companion diagnostics for the selection of the optimal immunosuppressive therapy programme for each patient.We have engaged all the partners we need for the development of the TRANSBIO project.We have designed the clinical study to be performed in the TRANSBIO study. It will imply two phases: 1) a pilot study and 2) a multicentre European validation study. We have submitted the documentation for the approval of the pilot clinical study by the pertinent Ethics Committee.FINANCIAL FEASIBILITY STUDY:We have calculated the total investment needed to reach a got to market stage. We have prepared a 5 years business plan by estimating the 5 years financial projections. We have analyzed the 5 years project profitability in different scenarios (base case, pessimistic and optimistic). Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora) The TRANSBIO project will bring to the healthcare market a unique solution for efficient management of renal transplanted patients. The TRANSBIO solution will enable the following novelties in patient care:Reducing chronic rejection by the early identification of patients at risk of this immunologic response. Early diagnosis of chronic rejection will open the possibility for clinicians to make the necessary adjustments in immunosuppressive therapy, as a way to avoid organ rejection to actually take place. Eliminating the side effects of immunosuppressant drugs in patients showing operational tolerance to the transplanted organ, by enabling total withdrawal of the immunosuppressive medication.Reducing the side effects of ineffective immunosuppressant therapies in all patients by enabling the determination of the optimal therapy for each patient (personalized medicine) and efficiently monitoring the immune response profile along time. Considering that more than 3.2 million people are diagnosed each year from End Stage Kidney disease (ESKD) and that renal replacement therapy is the treatment of choice for these patients, with an average worldwide prevalence of 450 p.m.p (3.28 million people living with a translated kidney worldwide), the social impact of the TRANSBIO project will be huge. Thanks to TRANSBIO these patients will enjoy an improved quality of life with reduced mortality likelihood. Besides the huge social impact expected by significant improvement of patients quality of life and reduction of ESKD mortality, the TRANSBIO project will also contribute to a more sustainable healthcare system. It is estimated that rejection of a transplanted kidney costs about 138.000€ per patient solely during the first year after graft failure. Therefore, if about 50% of transplanted organs are rejected in less than 10 years after transplantation, the total costs amount €226 billion worldwide. If the TRANSBIO test was implemented solely in management of 1% of patients worldwide (32.800 patients), and even if only a 50% of the total organ rejections were avoided (8.200 rejections), we might be talking of savings of more than €1.31 billion. Moreover, savings from TRANSBIO will also come from withdrawal of immunosuppressive therapy in operational tolerance cases (10% of patients). The average conservatively estimated yearly cost of immunosuppression medications is €8.000,1 so if a 10% of the 32.800 patients tested by TRANSBIO (3.280) are withdrawn from this medication, savings will amount €26.2M annually.