Defining stratification of patients with C3G/IC-MPGN complex mediated glomerular diseases for better diagnosis and tailored treatment

Primary membranoproliferative glomerulonephritis represents a group of rare kidney disorders associated with complement activation. There is no specific therapy and the prognosis is unfavorable: about half of all patients, mostly children, develop end-stage renal disease and need dialysis within 10 years of onset. MPGN is heterogeneous and patients have abnormal activation at different levels of the complement system. Several drugs targeting complement have been already approved or are investigated in trials for other conditions. However, trials to test new therapeutics will be heavily influenced by the heterogeneity MPGN. The current classification into C3 glomerulopathy (C3G) and immunecomplex- mediated MPGN (IC-MPGN) based on only histological data, does not reflect the etiology and is inefficient. Thus, there is an obligation in future trials to ensure that each patient is maximally characterized in order to receive the right drug. Previous studies identified four patient clusters, instrumental to define early and late complement activation. DECODE combined omics approaches (i.e. WES, proteomics and metabolomics) and hierarchical clustering analysis to define a precise stratification of patients with C3G/IC-MPGN, and to identify specific biomarkers, which will be instrumental for diagnosis, predicting prognosis and tailoring the right therapeutic strategy for the right patients. The project has developed a computational tool that will allow assignment of patients to a cluster using a limited set of genetic, thus saving resources and time. It has also refined the design of five clusters and increased the understanding of what treatment strategies may work best for which groups of patients. The project has developed 4 clinical trial protocols that can be used in future clinical trials. The Norwegian Institute of Public Health led work package 5 (WP5) in the project (Ethics and Society). The work package had several large deliveries. Between September 2022 and February 2023, Work Package 5 (WP5) of the DECODE project conducted the IMPACT survey to survey the views of adult patients diagnosed with MPGN and parents of patients, regarding potential participation in future clinical trials. 130 people from Europe and other areas of the world responded to the survey. The results show that most respondents would be willing to participate, or allow their child to participate, in a future clinical trial to test a new drug. Several factors such as expected side effects, the number of biopsies and the amount of time required to participate in the study were considered important. A report summarizing the findings is available on DECODE's website. In addition, WP5 has conducted semi-structured digital interviews with an international sample of MPGN patients and parents of MPGN patients to understand how they would make a possible future decision to participate in future clinical trials. Six main factors influenced the decision-making process: study design and practical aspects, personal motivation, concerns about participation, expert advice, current medical condition and family situation. The results are described in a scientific article published in the journal Rare. WP5 has also developed a guideline for informed consent in clinical trials for MPGN. The guideline is relevant for researchers, patient representatives and other stakeholders involved in the planning and conduct of clinical trials for MPGN. It provides comprehensive and tailored guidance regarding which information to provide to potential participants in multi-site clinical trials for MPGN under the informed consent process as well as links to relevant toolboxes. The guideline was developed to align with the ethical and legal requirements outlined in the EU Clinical Trial Regulation and the General Data Protection Regulation. The guideline is available on the DECODE website.

The project has developed a computational tool that will allow assignment of patients to a cluster using a limited set of genetic, thus saving resources and time. It has also refined the design of five clusters and increased the understanding of what treatment strategies may work best for which groups of patients. The project has developed 4 clinical trial protocols that can be used in future clinical trials. In WP5, the IMPACT survey has provided new insights into which factors influence MPGN patients' decision to participate or not in clinical trials. These new findings will help researchers design future clinical trials that are best suited to address patient needs, and may positively impact recruitment and retention rates. The guideline for informed consent in clinical trials for MPGN developed by WP6 provides useful information to researchers, patient representatives and other stakeholders involved in the planning and conduct of clinical trials for MPGN. It includes tailored guidance regarding which information to provide to potential participants in multi-site clinical trials for MPGN under the informed consent process as well as links to relevant toolboxes. Using this guideline may help researchers design information documents and tools that are better suited to address patient needs.

Primary membranoproliferative glomerulonephritis represents a heterogenous group of rare kidney disorders classified into alternative pathway complement-mediated C3 glomerulopathy (C3G) and immune-complex-mediated MPGN (IC-MPGN). These diseases are untreatable at the moment despite a plethora of complement inhibitors developed by many companies boosted by the success of the C5 inhibitor eculizumab that was literally transformative of the natural history of patients with atypical HUS. In the hope that the same could apply to patients with MPGN the main goal of DECODE is to improve the diagnosis and management of these very patients through precise stratification and tailored treatment protocols. Previous studies by the Coordinator have been capable of identifying four patient clusters, instrumental to define early and late complement activation. Building on this previous experience, here we will implement this strategy by combining omics approaches (i.e. WES, proteomics and metabolomics) and hierarchical clustering analysis to define a precise stratification of patients with C3G/IC-MPGN, and to identify specific biomarkers, which will be instrumental for diagnosis, predicting prognosis and tailoring the right therapeutic strategy for the right patients, towards personalized medicine. This proposal will offer also the unique opportunity to study a larger cohort of patients that will be in depth characterized for genetic and immune abnormalities in the various complement components, and for their clinical and biochemical characteristics.Specific objectives are: 1) stratify patients into clusters and provide easy to handle platform to assign patients to each them; 2) identify novel biomarkers of each cluster; 3) identify cluster specific therapies, and 4) design phase 2 clinical protocols. DECODE will involve end users and engage with regulator and decision makers to ensure maximum exploitation and impact, taking into account ethical, legal and social implications.