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

Stratifying patients with glomerulopathies for better Diagnosis and tailored treatment (DECODE) 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 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. As of December 2022, 295 patients with C3G/IC-MPGN have been identified and fully characterized (genetics, immunology, biochemical tests). Cluster analysis have been performed and 5 clusters identified. Proteomics analysis is ongoing. A patient survey to investigate perspectives regarding participation in future clinical studies was launched in the autumn of 2022 and responses from more than 100 patients in Italy, the Netherlands, Germany and Great Britain have been collected so far.

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.