3.1 Publishable summary

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1 3.1 Publishable summary This section must be of suitable quality to enable direct publication by the Commission. A summary description of project context and objectives, 4000 characters max The central focus of the BIO-DrIM project is the implementation of biomarker-driven strategies for personalizing immunosuppression (IS) in order to improve the long-term outcome and to decrease the adverse effects (graft toxicity, diabetes, cardiovascular events, opportunistic and community acquired infections, bone loss, and malignancies) and costs of chronic IS in solid organ transplant patients. The mission of the BIO-DrIM reflects the new strategy in the field of solid organ transplantation: leaving the path of one-size-fits-all weaning strategies and administration of new drugs in favour to a more personalized approach. The biomarker-guided management of immunosuppressive therapy is an ambitious program that started time ago with other projects (IOT and RISET) in which a set of promising biomarkers was identified and developed, but the methodical validation was missing. Implementation of these biomarkers into the clinical routine requires multiple cross platform tests, high quality standardization, multicenter clinical validation and with this an international network. All these requirements meet up in the BIO-DrIM project, that includes 5 innovative clinical trials (~1.800 patients in screening phase and ~1.000 patients enrolled in trials). More in detail, the BIO-DrIM project addresses several highly innovative issues: - First IS withdrawal study in long-term liver transplant patients based on the presence of a molecular tolerance signature (personalized withdrawal study 1); - Two novel trials on systematic partial IS withdrawal in selected highly stable long-term kidney transplant patients for validation of decision making biomarkers to detect operationally tolerant patients (personalized withdrawal- studies 2+3); - First controlled biomarker-driven perioperative stratification of kidney transplant patients into low/high responders to prevent high-dose standard IS in low responders (personalized minimizing IS study 4) - Novel approach to target selectively activated (allospecific) memory/effector T cells (to increase the proportion of low responders after kidney transplantation suitable for low-dose monotherapy validation by biomarkers study 5 Safety is a key issue of the clinical trials: all studies are performed according to the international rules and all drugs are used according to their applications. In addition to the well-validated set-1 biomarkers used for decision-making, all trials are accompanied by a panel of standardized biomarkers (set-2a) and a panel of exploratory biomarkers (set-2b): i) to further improve the predictive value of the biomarkers for patient stratification ii) to learn more about the mechanisms behind success/failure of IS minimizing. Gaining knowledge about the mechanisms behind successful weaning (regulation/effector balance) is also part of the project. Well-defined in vitro and experimental mouse/rat transplant studies will

2 be used to address questions regarding the mechanisms of success/failure of IS minimizing. In particular, the scientists within BIO-DrIM will address the interaction between regulatory pathways and donor-reactive memory/effector T cells. The research and trials planned in BIO-DrIM are strongly translational. The involvement of SME s and pharmaceutical industry guarantees a fast commercialization of promising product candidates. Furthermore, health-economic studies will push forward the translation into products used at the market as reimbursement strategies can be early developed and discussed with the health insurance companies and the government authorities. A description of the work performed since the beginning of the project and the main results achieved so far 4000 characters max The main results achieved till now are: 1. Set-up and validation of all tests of the biomarker panel; Figure 1: Biomarker panel. 2. Establishment of the ELISPOT technique, for the very first time, as stratification tool in a prospective trial. The test is now implemented and validated in all (n=8) the study centres. The ELISPOT categorizes patients into high / low responders with a cut-off of 25 spots/ cells. Correct patient categorization into high/low responders has successfully been confirmed during interlab comparisons. 3. Preparation of five multicenter clinical studies with more than 1000 patients. LIFT Study (WPIa; biomarker-based weaning of liver transplant patients): At the beginning of 2015 the LIFT Study (figure 2), coordinated by KCL, was approved by the UK authorities. Operational tolerant patients suitable for weaning will be identified based on intra graft gene expression. The LIFT Trial will be initiated at King s College Hospital in November 2015, and by 1 st December the first 5 patients will already be enrolled. It is expected that the remaining 10 clinical sites will be opened by February 2016.

3 CNI dose Clinical Eligibility Screening N = 592 Diagnosis of Biomarker Randomisation 1:1 N = A WEANING ALL STRATEGY N = 74 B BIOMARKER BASED WEANING STRATEGY N = 74 ~50% Expected Biomarker + ~50% Expected Biomarker A WEANING (N=74) All patients satisfying clinical criteria will be weaned off IS irrespective of biomarker result B+ WEANING ((N~37) Patients with a positive biomarker will be weaned off IS. B- MAINTENANCE IMMUNOSUPPRESSION (N~37) Patients with a negative biomarker test result will be informed of the result and will remain on IS. Figure 2: LIFT Study design. WEANING trial (WPIb; weaning of long-term stable kidney transplant patients): The fully blinded WEANING trial (figure 3), coordinated by ITUN (Nantes), had to be stopped after a very difficult restart when approved for further continuation. We expect to retrieve very interesting biological material and data from this important trial. Double Blind Randomized Study n = Screening (d-30) Inclusion (-1/3) Decreasing doses of Tacrolimus Month 0-2: -1/3 Month 2-4: -1/3 Month 4: TOTAL WEANNING Follow up every 15 days (renal function, proteinuria) 18 months follow up (12 months after CNI withdrawal) => Total study: 35 months 75 1/3 + Prograf n = /3 1/3 Transplantation 25 Prograf withdrawal Monotherapy cellcept +/-CS months > 4 years d0 Figure 3: WEANING Study design Study III trial (WPIc):

4 The Study III, coordinated by KCL, is a safety and feasibility pilot Phase II trial for initiating IS minimization in patients who score tolerant. Discussion on the tolerance signature with the scientific community will start soon. Figure 4: WEANING Study design CELLIMIN trial (WPII; FIH based trial using a biomarker as stratificator for IS): The CELLIMIN trial has been approved by the Voluntary-Harmonization Process (VHP). CELLIMIN is a non-inferiority trial with enrichment design aiming to demonstrate the utility and IFN- ELISPOT marker for the stratification of kidney transplant recipients into low and standard-of-care IS regimen. The coordinating centres are Barcelona and Berlin. Figure 5: CELLIMIN Study Design RIMINI trial (WPIII):

5 The RIMINI trial (former: ICARUS 2.0 ) is a single-arm Simon s two-stage Phase II clinical trial aiming to provide evidence for efficacy and safety of the induction regimen with ratg and infliximab and a go/no go rule for further clinical development. All documents are being prepared for VHP submission at the beginning of Figure 6: RIMINI Study design. 4. Mechanistic studies on animal models of transplantations were implemented by the groups of Nantes and Oxford for a deeply understanding of the ratio of memory T cells:naïve T cells, which clearly represent a challenge for minimizing IS. The last major achievement of BIO-DrIM is the involvement of two big pharma companies in the consortium. In October 2014 an agreement with TEVA was signed for supporting one of the clinical trials. It is the 1st time that a big pharma contributes to personalized IS studies. Dissemination activities were implemented and the consortium is very active on it. The consortium met several unexpected challenges but the collaboration within the groups was very supportive and allowed the achievements of several important milestones. We are, indeed, on the way to a more personalized IS therapy. The expected final results and their potential impact and use (including the socioeconomic impact and the wider societal implications of the project so far) characters max The focus of BIO-DrIM is to contribute to an improved and cost-effective long-term outcome of solid organ transplantation by implementing decision-making biomarkers into the clinical management of transplant patients (personalized IS) but the results will be more broadly relevant also to other ancillary disciplines and have very important exploitable potential. At this aim, three

6 research performing SMEs and two big companies are involved in the project with very deep commitment. Despite the progress in short-term organ transplant survival, long-term graft and patient survival remain almost unchanged and unsatisfactory. Our data suggest that about % of stable longterm kidney transplant patients express the full or partial tolerance signature suggesting opportunities for (partial) weaning. Additionally, even in any stable drug-free transplant patient, rejection can be suddenly triggered by immune activation, such as infection, even after years. Thus, there is a high unmet need for well validated biomarkers helping to identify operationally tolerant transplant patients and to monitor the stability of this situation. Low responders, requiring low-dose IS from beginning, exist already early after transplantation. To identify low responder patients to avoid unnecessary high-dose IS would have major advantage for this subset of patients. Based on our preliminary work we will address this topic by switching from one-size-fits-all IS to a stratified IS peri-transplant. Moreover, donor-specific memory/effector T cells were identified as the bad guys making transplant recipients to high-responders and preventing safe early IS minimization. To target selectively these cells resulting in a switch from high to low responder state would allow early IS minimization in a much higher population. This would have a major impact on costs and adverse effects in the majority of transplant recipients. IS in transplant patients has an EU/US market of about 3 Bill. /a personalized IS protocols have a big chance to dominate the IS market; and to expand to the huge autoimmunity market. The most important impact of this proposal is the personalization of immunosuppressive therapy in organ transplant recipients, thereby significantly improving their survival and quality of life, while at the same time decreasing health care costs. Secondarily, the results of BIO-DrIM will broadly impact the treatment of other disease related to undesired immune reactions, such as autoimmune diseases and graft-versus-host disease after hematopoetic stem cell transplantation. In addition, it might have also impact for the new field of cell transplantation (e.g. adult differentiated cells, like hepatocytes; but also allogeneic stem-cell derived cell products). In other words diseases with chronic or repetitive IS treatment. The novelty of this proposal is the stratification of transplanted patients regarding their individual immunological responsiveness to the allograft and their respective individual need of IS. A second area of novelty is the integrative design of this program, whereby a direct comparison (feasibility, safety, cost and promise of effect) of biomarkers driven strategies for personalized therapies is foreseen in 5 innovative investigator-driven biomarker clinical trials designed by the consortium with >1,800/1,000 patients screened/enrolled, respectively (liver and kidney transplant patients) These outputs have a strong potential for further commercial exploitation, with the expectation that personalized therapy can ultimately optimize the need for immunosuppressive drugs in organ transplant recipients. The address of the project public website, if applicable